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 .
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. Applicant has not complied with one or more conditions for receiving the benefit of an earlier filing date under 35 U.S.C. 119(e) as follows:
The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112, except for the best mode requirement. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
The disclosure of the prior-filed application, Application No. 62/943,166, fails to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application.
Although the specification provides support for soluble tetravalent γδ activators in the generic (see, for example, Pg. 5, last ¶), the claims and examples of relate to in vivo methods of expanding γδ T cells (see all claims of ‘166 and Examples 1-3, Pg. 84-86). While the specification proffers the hypothesis that higher-valency activators may improve the efficacy of the disclosed in vivo method (Pg. 86, ¶3), the disclosed ex vivo/in vitro methods of expansion describe the use of immobilized (i.e. not soluble) monoclonal antibodies (i.e. bivalent) (see § Ex-vivo Expansion of γδ T-cells, Pg. 42-53).
Accordingly, Claims 1-5, 8-11, 13-19, 21, 24-28, and 30-41, each drawn to an ex vivo method of selective γδ expansion comprising contacting isolated cells with a soluble tetravalent agent, are not entitled to the benefit of the prior application 62/943,166.
Earliest support for the claimed subject matter can be found in the international application PCT/US2020/063177 filed on 12/03/2020. Accordingly, the priority date for pending Claims 1-5, 8-11, 13-19, 21, 24-28, and 30-41 is considered to be 12/03/2020.
Election/Restrictions
Applicant’s election without traverse of the invention of Group I and a species of target cell comprising the δ1 and antigen binding site comprising the complete set of CDRs of antibody δ1-35 in the reply filed on 09/16/2025 is acknowledged.
Regarding Applicant’s election an antigen binding site comprising the complete set of CDRs of antibody δ1-35, Applicant asserts that “[a]t least claims 1-5, 8-11, 13-19, and 33-41” (Remarks; Pg. 10) encompass the elected species. However, upon review of the claims, each of Claims 10 and 16-19 read on antigen binding sites different from the elected species or having properties not possessed by the elected species.
Jakobovits et al. 2017 (WO 2017/197347 A1; PTO-892) previously disclosed the elected δ1-35 antibody and performed epitope mapping for δ1-35, as well as several other antibodies to γδ TCRs. According to Jakobovits, δ1-35 is specific to δ1 (i.e. not a “pan” γδ antibody) and recognizes a different epitope than antibodies TS-1 or TS8.2 (Fig. 47; Pg. 154, lines 19-30; Pg. 116, lines 27-28). Accordingly, Claim 10, drawn to a “pan” MAb, Claim 19, drawn to a MAb that cross-reacts with δ1 and δ3, and Claims 16-18, drawn to antibodies TS-1 and TS8.2 and/or antibodies binding the same epitope are not encompassed by the elected species of an antigen binding site comprising the complete set of CDRs of antibody δ1-35.
Claims 42, 44-46, 48-54, 56, 59-63, and 65-67 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, and Claims 10, 16-19, 21, 24-28, and 30-32 are withdrawn from further consideration as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 09/16/2025.
Claims 1-5, 9, 11, 13-15, and 33-41 are pending and are examined on the merits.
Drawings
The drawings are objected to because:
Fig. 23-25 is objected to because the sequence appears to correspond to a construct comprising the “Pan07” binding domain, but the annotation/legend of Fig. 23-25 (cont.) (sheets 43, 45, 48) provide the numbering for a “Pan05” binder, corresponding to the sequences shown in Fig. 20-22.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Claim Rejections - 35 USC § 112
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 38-41 are is 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.
Claim 38 and dependent Claims 39-41 are rejected for the phrase “preferably” followed by a narrower recitation of the claim or additional limitations. Specifically, Claim 38 recites “preferably wherein the administered population of γδ T cells comprises at least 60% γδ T cells”. The claims are considered indefinite because there is a question or doubt as to whether the additional limitations following “preferably” are (a) merely exemplary of a preferred embodiment, and therefore not required, or (b) a required feature of the claim.
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 38-41 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claims 38-41 depend directly or indirectly from Claim 36. Claim 36 requires that the γδ T cells are engineered to express tumor recognition moieties and/or secreted cytokines. Claims 38-41, however, encompass a method comprising administering “non-engineered γδ T cells”, and therefore each claim fails to include all of the limitations of Claim 36.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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 1-5, 9, 13, 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(s) 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. This is a written description rejection.
Scope of the claimed genus
Claims 1-5 and 9 are drawn to a method of selectively activating γδ T cells comprising contacting said cells with an unspecified “soluble multivalent agent” limited functionally by their ability to activate and expand said cells through binding of a γδ TCR epitope, wherein the only structural requirement is that the “soluble multivalent agent is at least tetravalent”. Claims 11, 13, and 15 further narrow the epitope to which the unspecified “soluble multivalent agent” binds (e.g. “the same epitope as antibody...δ1-35”), but fails to specify additional structural limitations to said agent.
Accordingly, the breadth of the claims is massive, encompassing not only potentially countless δ1 antibodies, but also any class of molecule or binding agent (e.g. ligands, single domain antibodies, aptamers, etc.) provided they meet they can be made tetravalent and meet the functional limitations of binding δ1 and activating/expanding δ1 T cells.
State of the prior art
Jakobovits et al. 2017 (WO 2017/197347 A1; PTO-892) teaches a number of antibodies specific to δ1, comprehensive of those disclosed in Fig 1 of the instant application, and further teaches several putative epitopes to which these antibodies bind. However, the antibody arts are well known to be unpredictable, the sequence space and diversity of binders to any particular antigen is massive, and the functional relationship between the antibody variable chain sequences and their target antigens is difficult to establish a priori.
For example, Sela-Culang et al. 2013 (Frontiers in immunology 4 (2013): 302.; PTO-892) teaches that antigens lack intrinsic properties that clearly differentiate between epitopic and non-epitopic residues, and any part of the antigen surface my become part of an epitope under some circumstances (“Ab Epitope Prediction”; Pg. 2). In the same vein, Edwards et al. 2003 (Journal of molecular biology 334.1 (2003): 103-118.; PTO-892) endeavored to uncover the breadth of the structural diversity of antibodies a single antigen can give rise to.
Edwards employed a phage display library to screen for antibodies that bind a single protein, BLyS, and isolated over 1000 unique anti-BLyS antibodies, each comprising a different amino acid sequence (Abstract). These antibodies were structurally diverse, resulted from nearly all possible Vh, D, and Jh, germlines (Pg. 105; “Vh and Vl germline usage”), and comprised 568 distinct Vh CDR3 sequences, ranging in length from 5 to 25 amino acid residues (Fig. 4; “Vh CDR3 sequence diversity”; Pg. 105). Together, these works highlight that neither knowledge of the antigen sequence nor the antibody sequence is necessarily predictive of its function. Accordingly, the skilled artisan would be unable to envisage the structure of an antibody that binds a γδ TCR a priori given the current state of the antibody arts.
Further, it is not clear from the instant disclosure or the prior art that binding to the γδ alone is sufficient for any given “multivalent agent” to activate and expand a population of γδ T cells. For example, antibodies B1, and 11F2 are described in the instant specification as γδ antibodies “suitable for use in the soluble multivalent agents provided herein” (Pg. 29, ¶1). However, Dutta et al. 2017 (Frontiers in immunology, 8, 776.; PTO-892) reports that – as opposed to the instantly claimed activity of inducing γδ expansion – each B1 and 11F2 induce apoptosis of γδ T cells (Fig. 1A), that this apoptosis occurs regardless of whether the antibodies are immobilized or soluble (Fig. 2H), and that apoptosis is exacerbated upon addition of IL-2 (Fig. 2). Dutta further teaches this antibody-induced apoptosis of γδ T cells has been previously observed with antibody 7A5, a V-segment specific γδ antibody (Pg. 8, last ¶).
Description of representative species in the specification
MPEP § 2163 states that a “representative number of species” means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus.
The instant disclosure provides sequences for 27 species of δ1 antibodies, all of which were previously disclosed (see WO 2017/197347 A1; PTO-892). Notably, the δ1 antibodies of the disclosure encompass a diverse range of sequences sharing little identity between one another, particularly in CDRH3 (Fig. 1), Further, the claims are not limited to soluble multivalent agents comprising antibodies, and there is no disclosure of any other class of δ1 binding agent beyond conventional antibodies (e.g. sdAbs, aptamers, etc.). Given the immense breadth of the claims, and in view of the teachings of Edwards described above highlighting the massive repertoire or possible antibody species for any given antigen, disclosure of only 27 species of a single molecular class of binding agent fails to constitute a “representative number of species” belonging to the claimed genus.
Identifying characteristics and structure/function correlation
In the absence of a representative number of species, the written description requirement for a claimed genus may be satisfied 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 claimed genus. To meet this requirement in the instant case, the specification must describe structural features that the skilled artisan as of the effective filing date would have expected to convey the claimed binding and activation functions.
While epitope mapping for the δ1-specific binders disclosed in Fig. 1 had previously been conducted (see WO 2017/197347 A1; PTO-892), the instant disclosure provides no further characterization of these binding domains beyond what is already known in the prior art. Further, as mentioned above, the δ1 antibodies of the disclosure encompass a diverse range of seemingly unrelated sequences, particularly in CDRH3 (Fig. 1), and there is no disclosure of the relationship between the underlying CDR sequences and their capacity to bind the δ1 TCR and/or activate δ1 T cells. Moreover, the only δ1-specific tetravalent activators reduced to practice comprise the same “δ1-08” binding domains (Fig. 11-16). Given the general lack of guidance provided by the instant specification on the structural features necessary for a “soluble multivalent agent” to both bind and activate the δ1 TCR, and in view of lack of a representative number of species of such agents, the instant disclosure has not reasonably conveyed to one of ordinary skill in the art that applicant was in possession of the invention commensurate in scope with the claims.
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.
Claims 1-5, 8-9, 11, 13-15, 33-36, and 38-41 are rejected under 35 U.S.C. 103 as being unpatentable over Jakobovits et al. 2017 (WO 2017/197347 A1; PTO-892), herein “Jakobovits”, and in view of Kokaji 2016 (US 2016/0068811 A1; PTO-892), herein “Kokaji”.
Jakobovits teaches a method of selectively expanding and enriching for a subpopulation of γδ1 T cells from an isolated mixture of peripheral blood mononuclear cells comprising contacting said cells with immobilized “δ1-35” antibody, an activating antibody specific for the variable region of the δ1 TCR (Pg. 154, lines 19-21), resulting in 48,933-fold expansion and 90% purity of γδ1 T cells from a starting population of 0.4% (Pg. 145-147, Example 49a; Fig. 43).
Regarding instant Claim 9, Jakobovits teaches that the method further encompasses contacting the cells with “one or more” first and second δ1 activating agents (Jakobovits claims 54-55) and that “the Mabs can bind to different epitopes on the constant or variable regions of γ TCR and/or δ TCR” (Pg. 47, lines 24-26).
Regarding instant Claims 13-15, the δ1-35 antibody of Jakobovits is the same as the “δ1-35” of the instant disclosure, and therefore comprises the same CDRs and binds the same δ1 epitope (compare sequences in Jakobovits Fig. 33-34 with those of instant Fig. 1-2).
Regarding instant Claims 33-34, Jakobovits teaches that the cells are expanded in a medium supplemented with cytokine, including, for example, IL-2 (Pg. 9, line 24 – Pg. 10, line 11; Pg. 141, Example 43).
Regarding instant Claims 35-36, Jakobovits teaches that the γδ T cells are further engineered to express tumor recognition moieties (Fig. 1; § Engineered γδ T cells, Pg. 60-70).
Regarding instant Claim 38, Jakbovits teaches the expanded/enriched engineered γδ T cells are administered to a subject in need thereof (Pg. 88; Fig. 2-3).
Regarding instant Claim 40, Jakobovits teaches that γδ T cells can be made with universal donor characteristics and can be administered allogenic to various subjects with different MHC haplotypes (Pg. 89, lines 1-3).
Regarding instant Claim 41, Jakobovits teaches the method of expanding γδ T cells can further comprise an αβ T cell depletion step following the γδ activation and expansion (Example 45, Pg. 142-143).
Jakobovits does not teach that the antibody is provided in a soluble tetravalent format. This deficiency is cured by Kokaji.
Kokaji teaches a method of activating and expanding T cells ex vivo comprising contacting isolated T cells with a soluble tetrameric antibody complex (TAC) specific for a TCR antigen (CD3 and/or CD28) (Pg. 4, Example 1).
Kokaji teaches that a TAC consists of two antibodies of one species (e.g. mouse-anti-CD3) bound together by two antibodies specific for the Fc region of the first two antibodies (rat anti-mouse IgG1) (¶0016; ¶0063). The resulting molecule would therefore be tetravalent for the TCR target (e.g. CD3 or CD28), as each constituent antibody is bivalent for its target antigen.
Kokaji teaches that soluble TACs provide several advantages over T cell activation using immobilized antibodies in that they do not require specialized antibody-coated plates or matrices and there is no need remove large magnetic particles (¶0013).
Regarding instant Claim 8, Kokaji teaches that monospecific TACs induced greater T cell proliferation when compared to bispecific TACs (Example 1; ¶0066; Fig. 1).
Kokaji further teaches that TACs perform comparably to immobilized antibody strategies in inducing T cell activation and proliferation (Figs. 2-5).
It would have been obvious to one of ordinary skill in the art to substitute the αβ TCR antibodies according to the method taught by Kokaji with the “δ1-35” antibody taught by Jakobovits to arrive at a method of selectively expanding δ1 T cells comprising contacting isolated cells ex vivo with a tetravalent activator comprising the CDRs of δ1-35. The skilled artisan would have been motivated to do so because Kokaji teaches that soluble tetrameric antibody complexes eliminate the need for specialized antibody-coated plates, like those employed by the method of Jakobovits. There would have been a reasonable expectation of success because Jakobovits teaches antibody δ1-35 induces high-purity expansion of δ1 T cells, and because Kokaji teaches that delivering T cell activating antibodies as soluble tetrameric complexes performs similarly to conventional immobilized antibody strategies.
Further, regarding instant Claim 39, Jakobovits is silent on whether the administered cells are autologous to the subject.
However, Jakobovits teaches that the disclosed γδ T cells “can be a universal donor for a human subject with any HLA haplotype” (Pg. 66, line 20). Jakobovits further teaches that the γδ T cells can be cryopreserved and stored for years prior to administering to a patient (§ Preservation, Pg. 101-102).
It would have been obvious to one of ordinary skill in the art that the γδ T cells expanded according to the combined teachings of Jakobovits and Kokaji above could be administered to the same subject from which they were isolated and expanded (i.e. allogenic). Because said cells are described as a “universal donor”, it would be obvious that this would be inclusive of the original host should said individual later develop a condition wherein administration of the cells would be beneficial (e.g. cancer). There would have been a reasonable expectation of success because Jakobovits teaches the engineered γδ T cells can be stored for years after expansion and administered to “any subject with any HLA haplotype”.
Claim 37 is rejected under 35 U.S.C. 103 as being unpatentable over Jakobovits et al. 2017 (WO 2017/197347 A1; PTO-892), herein “Jakobovits”, and Kokaji 2016 (US 2016/0068811 A1; PTO-892), herein “Kokaji”, as applied to claims 1 and 35-36 above, and further in view of Pegram et al. 2014 (The Cancer Journal, 20(2), 127-133.; PTO-892), herein “Pegram”.
The teachings of Jakobovits and Kokaji are summarized above.
Jakobovits and Kokaji do not teach that the γδ T cells are engineered to express IL-15 from a transgene. This deficiency is cured by Pegram.
Pegram teaches that T cells such as those expressing a γδ TCR can be further modified to express tumor-targeting CARs and secreted cytokines, such as IL-15 (Fig. 1). Pegram teaches that T cells engineered to constitutively produce IL-15 from a transgene are ideal for adoptive transfer therapy owing to their enhanced proliferation and resistance to apoptosis (Pg. 5, § IL-15), and that concerns about the leukemogenic potential of such engineered T cells can be mitigated by including a suicide gene as a safety switch (Pg. 6, ¶2).
It would have been obvious to one of ordinary skill in the art that the combined method of Jakobovits and Kokaji described above could further include γδ T cells engineered to express an exogenous secreted cytokine, such as IL-15. The skilled artisan would have been motivated to include an IL-15 transgene to improve proliferation and survival of the therapeutic T cell population in a patient. There would have been a reasonable expectation of success because Pegram teaches T cells modified with an exogenous IL-15 transgene maintained proliferative capacity with additional exogenous cytokines, and that suicide genes can be introduced to prevent instances of uncontrolled proliferation.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-5, 8, 13-15, 35-36, 38, 41 rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3 and 5-15 of U.S. Patent No. 11,299,708 in view of Kokaji 2016 (US 2016/0068811 A1), herein “Kokaji”.
Regarding instant Claims 1-5, 8, and 13-15, the claims of ‘708 are drawn to an ex vivo method of producing an enriched γδ T cell population from an isolated mixed cell population comprising contacting the mixed cell population with an antibody that binds an epitope specific to the δ1 variable region of a δ1 TCR wherein the antibody comprises a variable heavy chain corresponding to ‘708 SEQ ID NO: 158 and a variable light chain corresponding to ‘708 SEQ ID NO: 185 (‘708 claim 1) (which are identical to instant the VH/VL of instantly claimed antibody “δ1-35”, SEQ ID NOs: 6 and 33, respectively – see alignment below).
δ1-35 VH
SEQ6 1 EVQLQQSGTVLARPGSSVKMSCKASGYTFTTYWMHWVKQRPGQGLDWIGAIYPGNSDTNY 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
‘708-158 1 EVQLQQSGTVLARPGSSVKMSCKASGYTFTTYWMHWVKQRPGQGLDWIGAIYPGNSDTNY 60
SEQ6 61 NQKFRGKAKLTAVTSASTAYMELSSLTNEDSAVYYCTYGYYVDYYAMDYWGQGTSVTVSS 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
‘708-158 61 NQKFRGKAKLTAVTSASTAYMELSSLTNEDSAVYYCTYGYYVDYYAMDYWGQGTSVTVSS 120
δ1-35 VL
SEQ33 1 DIVMTQSHKFMSTSVGDRVSITCKASQDVSIDVAWYQQKPGQSPKLLIYSASYRYTGVPD 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
‘708-185 1 DIVMTQSHKFMSTSVGDRVSITCKASQDVSIDVAWYQQKPGQSPKLLIYSASYRYTGVPD 60
SEQ33 61 RFTGSGSGTDFTFTISNVQAEDLAVYYCQQHYSIPCTFGSGTKLEIK 107
|||||||||||||||||||||||||||||||||||||||||||||||
708-185 61 RFTGSGSGTDFTFTISNVQAEDLAVYYCQQHYSIPCTFGSGTKLEIK 107
Regarding instant Claim 35-36, ‘708 claim 9 is drawn to a method wherein the δ1 T cell population is further engineered to express one or more tumor recognition moieties.
Regarding instant Claim 38, ‘708 claims 2 and 7 are drawn to the method wherein the enriched T cell population is greater than 60% δ1 T cell and wherein the T cell population is further formulated for administration to a subject.
Regarding instant Claim 41, ‘708 claim 11 is drawn to a method further comprising depleting αβ T cells.
The claims of ‘708 are not drawn to a method wherein the δ1 activating antibody is provided in a soluble tetravalent format. This deficiency is cured by Kokaji.
Kokaji teaches a method of activating and expanding T cells ex vivo comprising contacting isolated T cells with a soluble tetrameric antibody complex (TAC) specific for a TCR antigen (CD3 and/or CD28) (Pg. 4, Example 1).
Kokaji teaches that a TAC consists of two antibodies of one species (e.g. mouse-anti-CD3) bound together by two antibodies specific for the Fc region of the first two antibodies (rat anti-mouse IgG1) (¶0016; ¶0063). The resulting molecule would therefore be tetravalent for the TCR target (e.g. CD3 or CD28), as each constituent antibody is bivalent for its target antigen.
Kokaji teaches that soluble TACs provide several advantages over T cell activation using immobilized antibodies in that they do not require specialized antibody-coated plates or matrices and there is no need remove large magnetic particles (¶0013).
Regarding instant Claim 8, Kokaji teaches that monospecific TACs induced greater T cell proliferation when compared to bispecific TACs (Example 1; ¶0066; Fig. 1).
Kokaji further teaches that TACs perform comparably to immobilized antibody strategies in inducing T cell activation and proliferation (Figs. 2-5).
It would have been obvious to one of ordinary skill in the art to substitute the αβ TCR antibodies according to the method taught by Kokaji with the δ1 activating antibodies according to the claimed method of ‘708 to arrive at a method of selectively expanding δ1 T cells comprising contacting isolated cells ex vivo with a tetravalent activator comprising the CDRs of δ1-35. The skilled artisan would have been motivated to do so because Kokaji teaches that soluble tetrameric antibody complexes eliminate the need for specialized antibody-coated plates. There would have been a reasonable expectation of success because the claims of ‘708 are drawn to a method of activating δ1 T cells with δ1 specific antibody, and because Kokaji teaches that delivering T cell activating antibodies as soluble tetrameric complexes performs similarly to conventional immobilized antibody strategies.
Claims 9, 33-34 and 39-40 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3 and 5-15 of U.S. Patent No. 11,299,708 in view of Kokaji 2016 (US 2016/0068811 A1), herein “Kokaji”, as applied to 1-5, 8, 13-15, 35-36, 38, 41 above, and further in view of Jakobovits et al. 2017 (WO 2017/197347 A1; PTO-892), herein “Jakobovits”.
Note that the Jakobovits reference comprises the same disclosure as U.S. Patent No. 11,299,708.
The claims of ‘708 in view of Kokaji are summarized above.
The claims of ‘708 are not drawn to a method further comprising antigen binding sites binding to different epitopes (instant Claim 9), culturing in cytokine (instant Claims 33-34), nor wherein the cells are allogeneic (instant Claim 40) or autologous to a subject (instant claim 39).
These deficiencies are cured by Jakobovits.
Regarding instant Claim 9, Jakobovits teaches that the method further encompasses contacting the cells with “one or more” first and second δ1 activating agents (Jakobovits claims 54-55) and that “the Mabs can bind to different epitopes on the constant or variable regions of γ TCR and/or δ TCR” (Pg. 47, lines 24-26).
Regarding instant Claims 33-34, Jakobovits teaches that the cells are expanded in a medium supplemented with cytokine, including, for example, IL-2 (Pg. 9, line 24 – Pg. 10, line 11; Pg. 141, Example 43).
Regarding instant Claim 40, Jakobovits teaches that γδ T cells can be made with universal donor characteristics and can be administered allogeneic to various subjects with different MHC haplotypes (Pg. 89, lines 1-3).
It would have been obvious to one of ordinary skill in the art that the method as claimed in ‘708 could further encompass the limitations above, namely multiple antigen binding sites specific for different epitopes, exogenous cytokine in the culture media, and administering cells allogeneic to a subject, given that the Jakobovits reference comprises the same disclosure as U.S. Patent No. 11,299,708, and each of its teachings are in the context of the same method of expanding γδ T cells encompassed by the claims of ‘708.
Further, regarding instant Claim 39, Jakobovits is silent on whether the administered cells are autologous to the subject.
However, Jakobovits teaches that the disclosed γδ T cells “can be a universal donor for a human subject with any HLA haplotype” (Pg. 66, line 20). Jakobovits further teaches that the γδ T cells can be cryopreserved and stored for years prior to administering to a patient (§ Preservation, Pg. 101-102).
It would have been obvious to one of ordinary skill in the art that the γδ T cells expanded according to the claims of ‘708 and the combined teachings of Jakobovits and Kokaji above could be administered to the same subject from which they were isolated and expanded (i.e. allogenic). Because said cells are described as a “universal donor”, it would be obvious that this would be inclusive of the original host should said individual later develop a condition wherein administration of the cells would be beneficial (e.g. cancer). There would have been a reasonable expectation of success because Jakobovits teaches the engineered γδ T cells can be stored for years after expansion and administered to “any subject with any HLA haplotype”.
Claim 37 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3 and 5-15 of U.S. Patent No. 11,299,708 in view of Kokaji 2016 (US 2016/0068811 A1; PTO-892), herein “Kokaji”, as applied to 1-5, 8, 13-15, 35-36, 38, 41 above, and further in view of Pegram et al. 2014 (The Cancer Journal, 20(2), 127-133.; PTO-892), herein “Pegram”.
The claims of ‘708 in view of Kokaji are summarized above.
The claims of ‘708 in view of Kokaji are not drawn to γδ T cells engineered to express IL-15 from a transgene. This deficiency is cured by Pegram.
Pegram teaches that T cells such as those expressing a γδ TCR can be further modified to express tumor-targeting CARs and secreted cytokines, such as IL-15 (Fig. 1). Pegram teaches that T cells engineered to constitutively produce IL-15 from a transgene are ideal for adoptive transfer therapy owing to their enhanced proliferation and resistance to apoptosis (Pg. 5, § IL-15), and that concerns about the leukemogenic potential of such engineered T cells can be mitigated by including a suicide gene as a safety switch (Pg. 6, ¶2).
It would have been obvious to one of ordinary skill in the art that the method according to the claims of ‘708 in view of Kokaji described above could further include γδ T cells engineered to express an exogenous secreted cytokine, such as IL-15. The skilled artisan would have been motivated to include an IL-15 transgene to improve proliferation and survival of the therapeutic T cell population in a patient. There would have been a reasonable expectation of success because Pegram teaches T cells modified with an exogenous IL-15 transgene maintained proliferative capacity with additional exogenous cytokines, and that suicide genes can be introduced to prevent instances of uncontrolled proliferation.
Conclusion
No claim is allowed.
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/BRYAN WILLIAM HECK/ Examiner, Art Unit 1643
/JULIE WU/ Supervisory Patent Examiner, Art Unit 1643