DETAILED ACTION
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Applicant’s Request for Continued Examination, Amendment and Arguments/Remarks received on 09 September 2025 have been entered.
Claims 1-10, 19-26, 29, and 34 were previously pending. New claim 35 has been added by Applicant. Claims 1-10, 19-26, 29, and 34-35 are currently pending in the application. Claims 1, 19, and 29 are independent claims. The election of Group I, drawn to an antigen-density sensing molecular circuit, and method of activating an immune response to a target cell expressing an antigen in a subject, remains in effect in the instant application. The following election of species remains in effect in the instant application:
1) Binding-signal transduction domain: Notch force sensor cleavage domain.
Claims 19-26 remain withdrawn from consideration as being directed to a nonelected invention.
Claims 1-10, 29, and 34-35 are currently pending and under examination in the instant application. An action on the merits follows.
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA . The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Priority
The present application is a 35 U.S.C. 371 national stage filing of International Application No. PCT/US2019/053151, filed 26 September 2019, which claims priority to U.S. Provisional Application No. 62/738,995, filed 28 September 2018.
Thus, the earliest possible priority for the instant application is 28 September 2018.
PRIOR OBJECTIONS AND/OR REJECTIONS
Specification
The objection to the specification of the disclosure for the Brief Description of the Drawings not including a description of each of the panels within each figure for Figures 7 and 15-17 is withdrawn in view of the amendment to the specification.
Claim Rejections - 35 USC § 112(b)
The rejection of amended and previously presented claims 1-10, 29, and 34 under 35 U.S.C. 112(b) as failing to particularly point out and distinctly claim the subject matter which the inventor(s) regards as the invention for reciting “with second affinity that is at least 5 times higher than the second affinity”, is withdrawn in view of Applicant’s amendments to claim 1.
Claim Rejections - 35 USC § 103
The rejection of amended and previously presented claims 1-10, 29, and 34 under 35 U.S.C. 103 as being unpatentable over Wong (US20170183654A1), published 29 June 2017, in view of Roybal et al. 2016, Cell, Vol. 167, 419-432, IDS, and Cuesta et al. 2010, Trends in Biotechnology, Vol. 28, 355-362, is withdrawn in view of Applicant’s claims which now recite the co-expression of the antigen-triggered transcriptional switch and the antigen-specific therapeutic in the cell for cooperative recognition of the antigen.
Double Patenting
The rejection of amended and previously presented claims 1-10, 29, and 34 on the ground of nonstatutory double patenting as being unpatentable over claims 1-25 of U.S. Patent No. 10,836,808, hereafter referred to as the ‘808 patent, in view of Wong (US20170183654A1), published 29 June 2017, is withdrawn in view of Applicant’s claims which now recite the co-expression of the antigen-triggered transcriptional switch and the antigen-specific therapeutic in the cell for cooperative recognition of the antigen.
NEW OBJECTIONS AND/OR REJECTIONS
Claim Rejections - 35 USC § 112(a)- Scope of Enablement
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.
Amended, previously presented, and new claims 1-10, 29, and 34-35 are newly 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 T cell comprising:
an antigen-density sensing molecular circuit comprising:
a nucleic acid sequence encoding an antigen-triggered transcriptional switch that binds an antigen present on the surface of a target cell with a first affinity;
a nucleic acid sequence encoding an antigen-specific therapeutic that binds to the antigen with a second affinity that is at least 5 times higher than the first affinity, wherein the first and second affinities are each expressed as a dissociation constant (KD); and
a regulatory sequence operably linked to (b) that is activated by binding of the antigen-triggered transcriptional switch of (a) to the antigen to induce expression of the antigen-specific therapeutic of (b), thereby resulting in co-expression of the antigen-triggered transcriptional switch of (a) and the antigen-specific therapeutic of (b) in the cell,
wherein the antigen-triggered transcriptional switch of (a) and the antigen-specific therapeutic of (b) provide for cooperative recognition of the antigen;
wherein the antigen-triggered transcriptional switch is a synNotch receptor;
wherein the synNotch receptor comprises (i) an extracellular binding domain that comprises an antigen binding region of an antibody, (ii) a Notch force sensor cleavage domain, and (iii) an intracellular domain that comprises a DNA binding domain, wherein the intracellular domain does not comprise an immunoreceptor activation domain or a co-stimulatory domain, wherein binding of the antigen binding region of (a)(i) to an antigen induces proteolytic cleavage of the Notch receptor regulatory domain of (a)(ii) and releases the DNA binding domain of (a)(iii);
wherein the released DNA binding domain binds to the regulatory sequence; and
wherein the antigen-specific therapeutic is a chimeric antigen receptor (CAR), T cell receptor (TCR), or antibody;
-and-
a method of activating a response to a target cell expressing an antigen in a subject; the method comprising:
administering to the subject a cell of claim 1;
wherein the synNotch receptor expressed by the cell of claim 1 binds the antigen present on the surface of the target cell in the subject to induce expression of the antigen-specific therapeutic within the cell of claim 1;
does not reasonably provide enablement for:
any cell comprising an antigen-density sensing molecular circuit comprising:
(a) a nucleic acid sequence encoding any antigen-triggered transcriptional switch that binds any antigen present on the surface of any target cell with a first affinity;
(b) a nucleic acid sequence encoding any antigen-sensing therapeutic that binds to the antigen with a second affinity that is at least 5 times higher than the first affinity, wherein the first and second affinities are each expressed as a dissociation constant (KD); and
(c) any regulatory sequence operably linked to (b) that is activated by binding of the antigen-triggered transcriptional switch of (a) to the antigen to induce expression of the antigen-specific therapeutic of (b), thereby resulting in co-expression of the antigen-triggered transcriptional switch of (a) and the antigen-specific therapeutic of (b) in the cell,
wherein the antigen-triggered transcriptional switch of (a) and the antigen-specific therapeutic of (b) provide for cooperative recognition of the antigen;
- nor -
a method of activating any response to any target cell expressing any antigen in any subject; the method comprising administering to the subject any cell of claim 1.
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, use, and practice the invention commensurate in scope with these claims.
This rejection comprises four (4) separate issues: 1) the absence of an enabling disclosure for any cell comprising an antigen-density sensing molecular circuit other than a T cell; 2) the absence of an enabling disclosure for any antigen-triggered transcriptional switch other than a synNotch receptor wherein the synNotch receptor comprises (i) an extracellular binding domain that comprises an antigen binding region of an antibody, (ii) a Notch force sensor cleavage domain, and (iii) an intracellular domain that comprises a DNA binding domain, wherein the intracellular domain does not comprise an immunoreceptor activation domain or a co-stimulatory domain, wherein binding of the antigen binding region of (a)(i) to an antigen induces proteolytic cleavage of the Notch receptor regulatory domain of (a)(ii) and releases the DNA binding domain of (a)(iii), and wherein the released DNA binding domain binds to the regulatory sequence; 3) the absence of an enabling disclosure for any antigen-specific therapeutic other than a CAR, TCR, or antibody; and 4) the absence of an enabling disclosure for activating a response to a target cell expressing any antigen other than the antigen the cell of claim 1 is configured to bind.
These issues were identified by the Office after analysis of the disclosure provided by the specification. The Office has analyzed the specification in direct accordance to the factors outlined in In re Wands, namely 1) the nature of the invention, 2) the state of the prior art, 3) the predictability of the art, 4) the amount of direction or guidance present, and 5) the presence or absence of working examples, and presented detailed scientific reasons supported by publications from the prior art for the finding of a lack of enablement for the scope of the instant methods. The Wands analysis and supporting specific evidence are presented below for each of the identified issues.
As a first issue (1), the specification does not provide an enabling disclosure for any cell comprising an antigen-density sensing molecular circuit other than a T cell.
The broadest independent claim, claim 1, recites “a cell” in line 1. Claims 2-10 and 34-35 depend on claim 1. Independent claim 29 recites “a cell of claim 1” in line 3.
The specification discloses that suitable cells encoding the molecular circuits include immune cells [00187], immune stem cells, immune progenitor cells, stem cells, or progenitor cells [00188]. However, Example 1 of the specification teaches only the use of CD8+ synNotch-CAR T cells [00268-00269, 00271-00274, 00276-00285, 00294-00295, 00299-00304]. The specification further teaches that the CD8+ synNotch-CAR T cells comprising the antigen-density sensing molecular circuit function via cytotoxic target cell killing functions facilitated by the synNotch-induced expression of a CAR [0003, 0056, 00301-00303, Figure 2-4, 7, 10, 18, 22, 23, 25]. The specification does not provide any data for any cells other than CD8+ T cells comprising the antigen-density sensing molecular circuit.
The art at the time of filing teaches that chimeric antigen receptors (CARs) are synthetic receptors that reprogram T lymphocytes to target chosen antigens and reprogram T cell function, such that binding to antigen triggers T cell activation [Riviere & Sadelain 2017, Molecular Therapy, 25(5), 1117-1124, abstract, column 1 ¶ 1, column 4 ¶ 2- column 6 ¶ 2]. Riviere further teaches that lymphocyte engineering may be performed in lymphoid precursors, including T cell progenitors which then can be used to generate T cells, and that iPSC-derived T cells expressing a CAR can eradicate tumors in vivo [column 5 ¶ 2- column 6 ¶ 1]. However, Riviere does not teach that the T cell precursors themselves are functional for antigen sensing, which is necessary for the co-expression of the antigen-triggered transcriptional switch and antigen-specific therapeutic of the instantly claimed invention.
Roybal teaches synNotch receptors expressed in T cells sense tumor antigens and drive customized therapeutic responses for cancer and other diseases [Roybal et al. 2016, Cell, 167, 419-432, IDS, cited in a prior action, Highlights]. Roybal further teaches that relevant cell types for cell-based therapies include human CD4+ and CD8+ T cells [column 6 ¶ 2].
Neither the specification nor the art at the time of filing teaches to modify cells other than T cells or T cell precursors with antigen-specific therapeutics.
Thus, in view of the limited teachings in the art to modify only T cells or T cell precursors with antigen-specific therapeutics and/or synNotch receptors, the teachings in the art that CD4+ and CD8+ T cells are relevant cells types for cell-based therapies, Applicant’s limited teachings in the specification of only T cells comprising the antigen-density sensing molecular circuit, and the breadth of the claims, the skilled artisan would have considered any cell other than a T cell expressing an antigen-triggered transcriptional switch which, upon binding to a cell-surface antigen, activates expression of an antigen-specific therapeutic for cooperative recognition of the antigen and for activating a response to a target cell, as highly unpredictable. As such it would have required undue experimentation to practice the scope of applicant’s invention as claimed.
As a second issue (2), the specification does not provide an enabling disclosure for an antigen-triggered transcriptional switch other than a synNotch receptor, wherein the synNotch receptor comprises (i) an extracellular binding domain that comprises an antigen binding region of an antibody, (ii) a Notch force sensor cleavage domain, and (iii) an intracellular domain that comprises a DNA binding domain, wherein the intracellular domain does not comprise an immunoreceptor activation domain or a co-stimulatory domain, wherein binding of the antigen binding region of (a)(i) to an antigen induces proteolytic cleavage of the Notch receptor regulatory domain of (a)(ii) and releases the DNA binding domain of (a)(iii); and wherein the released DNA binding domain binds to the regulatory sequence.
The broadest independent claim, claim 1, recites a cell comprising an antigen-density sensing molecular circuit comprising (a) a nucleic acid encoding an antigen-triggered transcriptional switch that binds an antigen present on the surface of a target cell, and that expression of an antigen-specific therapeutic is induced upon binding of the antigen-triggered transcriptional switch to the antigen. Claims 2-10 and 34-35 depend on claim 1. Independent claim 29 recites a method of activating a response to a target cell expressing an antigen in a subject by administering to the subject a cell of claim 1.
The specification discloses antigen-triggered transcriptional switches which are synNotch polypeptides, MESA polypeptides, TANGO polypeptides, or vWF cleavage domain-based polypeptides, [00138-00139, 00148-00152, Figure 5, 7]. The specification specifically teaches the use of synNotch polypeptides, which the specification teaches include a) an extracellular domain comprising a specific binding member; b) a proteolytically cleavable Notch receptor polypeptide comprising one or more proteolytic cleavage sites, and c) an intracellular domain which, when cleaved secondary to antigen binding by the extracellular domain, induces the production of an encoded payload (e.g., the claimed antigen-specific therapeutic) [00153]. The working example, Example 1, only teaches the use of a HER2-targeted synNotch polypeptide (e.g., in a HER2 density sensing synNotch/CAR circuit) [00268, 00270-00271, 00274, 00276-00280, 00282-00285, 00292, 00299-00301, 00302-00304, Figure 7, 10, 11, 17-21, 23-26].
The art at the time of filing teaches that antigen recognition by T cells leads to an activation cascade in the T cell which includes transcription factors which induce the expression of cytokine genes through specific downstream signaling events, including the induction of the transcription factor NFAT [Cantrell 1996, Annual Review in Immunology, 14, 256-274, abstract, page 264 ¶ 2-page 265 ¶ 1]. Additionally, Zhang teaches a cell engineered to express a tumor antigen-specific TCR, which upon antigen binding, activates NFAT to induce expression of an IL-12 transgene controlled by an NFAT-responsive promoter [Zhang et al. 2011, Molecular Therapy, 19(4), 751-759, abstract]. Further, Roybal teaches antigen-triggered transcriptional switches which are synNotch receptor polypeptides, wherein the synNotch receptor senses tumor antigens and drives customized therapeutic responses, such as expression of cytokines, cytotoxic agents, adjuvants, or therapeutic antibodies [Roybal et al. 2016, Cell, 167, 419-432, IDS, cited in a prior action, Highlights, column 2 ¶ 3-column 3 ¶ 2]. Royal teaches that the cells comprising the synNotch receptor were further engineered to comprise the associated promoter (e.g., with 5x Gal4 response elements) controlling expression of the transgene of interest [column 5 ¶ 2]. Therefore, the art at the time of filing teaches that the antigen-dependent transcriptional activation is dependent upon specific signaling mechanisms which result in the specific activation of specific genes, wherein activation of a transgene can be accomplished by matching the operably linked regulatory sequences (e.g., promoters and/or enhancers) with the downstream signaling induced by antigen binding to the antigen-triggered transcriptional switch.
Neither the art at the time of filing nor the specification teach wherein any antigen-triggered transcriptional switch can induce expression of any transgene. Thus, in view of the specificity of antigen-triggered downstream signaling and transcriptional activation of a transgene, Applicant’s limited teachings of a single HER2 synNotch antigen-triggered transcriptional switch used in Applicant’s Example 1, and the breadth of the claims, the skilled artisan would have considered inducing expression of an antigen-specific therapeutic by binding of any antigen-triggered transcriptional switch to the antigen other than a synNotch polypeptide configured to activate expression by binding a regulatory sequence operably linked to a nucleic acid sequence encoding the antigen-specific therapeutic as highly unpredictable. As such it would have required undue experimentation to practice the scope of applicant’s invention as claimed.
As a third issue (3), the specification does not provide an enabling disclosure for an antigen-specific therapeutic other than a CAR, TCR, or antibody.
The broadest independent claim, claim 1, recites “an antigen-specific therapeutic that binds to the antigen” in line 5. Claims 2-10 and 34-35 depend on claim 1. Independent claim 29 recites a method of activating a response to a target cell expressing an antigen in a subject by administering to the subject a cell of claim 1.
The specification teaches that antigen-specific therapeutics useful in the methods of the present disclosure include CARs, TCRs, chimeric bispecific binding members, and therapeutic antibodies [00110, 00130]. The working example, Example 1, teaches only HER2 CAR constructs as the antigen-specific therapeutics [00276, 00278, 00281, 00301, Figure 6-8, 10, 15-16].
The art at the time of filing teaches that there are a various types of antigen-specific therapeutics, including therapeutic vaccination with antigen-specific Tregs to treat autoimmunity [Bluestone & Tang 2004, Proceedings of the National Academy of Science, 101(supplement 2), 14622-14626, title, abstract, column 5 ¶ 2, column 6 ¶ 1, 2, column 7 ¶ 2- column 8 ¶ 3]; oral administration of antigen, immunization with different epitopes derived from the same protein, dendritic cell vaccination, or siRNA-based immunotherapy and vaccination for antigen-specific tolerance induction [Ichim et al. 2008, Expert Opinion on Biological Therapy, 8(2), 191-199, abstract, column 3 ¶ 3- column 4 ¶ 1, column 5 ¶ 2- column 6 ¶ 1, column 7 ¶ 3, column 8 ¶ 2]; and antigen-specific vaccination for cancer treatment (e.g., vaccination with whole tumor cell preparations, peptide-proteins, dendritic cells, nucleic acids/ viral vectors) [Tagliamonte et al. 2014, Human Vaccines & Immunotherapeutics, 10(11), 3332-3346, abstract, column 2 ¶ 4-5, column 5 ¶ 4, column 8 ¶ 2, column 11 ¶ 3-column 13 ¶ 4].
Neither the specification nor the art at the time of filing teaches that antigen-density sensing molecular circuits can comprise a nucleic acid encoding any antigen-specific therapeutic that binds to the antigen. Thus, in view of the limited teachings in the specification for antigen-specific therapeutics which are CARs, TCRs, or antibodies; the numerous types of antigen-specific therapeutics known in the art, and the breadth of the claims, the skilled artisan would have considered making and using an antigen-density sensing molecular circuit which comprises a nucleic acid encoding any antigen-specific therapeutic that binds to the antigen as highly unpredictable. As such it would have required undue experimentation to practice the scope of applicant’s invention as claimed.
As a fourth issue (4), the specification does not provide an enabling disclosure for activating a response to a target cell expressing any antigen other than the antigen the cell of claim 1 is configured to bind. Independent claim 29 recites a method of activating a response to a target cell expressing an antigen in a subject, the method comprising administering to the subject a cell of claim 1.
The specification teaches activating responses (e.g., a transcriptional response) to a target cell expressing an antigen on its surface (e.g., HER2), wherein the synNotch receptor binds specifically to the particular antigen (E.g., HER2) expressed on the target cell surface [Example 1, Figure 3, 4, 5, 7, 8].
The art at the time of filing teaches synNotch receptors configured to recognize specific antigens (e.g., GFP, CD19) on the surface of a target cell and to thereby activate a response to the target cell (e.g., a transcriptional response) [Roybal et al. 2016, Cell, 167, 419-432, IDS, cited in a prior action, Highlights, column 2 ¶ 3-column 3 ¶ 2, Figure 4, 5].
Neither the specification nor the art at the time of filing teaches that administration of a cell comprising an antigen-density sensing molecular circuit specific to a particular antigen can induce a response to any other antigen. Thus, in view of the specificity of binding for antigen-binding moieties, the teachings in the art and the specification of antigen-specific responses induced only by the specific antigen, and the breadth of the claims, an ordinarily skilled artisan at the time of filing would have considered activating a response to a target cell expressing any antigen in a subject by administration of a cell configured to recognize a specific antigen as highly unpredictable. As such it would have required undue experimentation to practice the scope of applicant’s invention as claimed.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Dr. KATIE L PENNINGTON whose telephone number is (703)756-4622. The examiner can normally be reached M-Th 8:30 am - 5:30 pm, Friday 8:30 am - 12:30 pm CT.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Maria G. Leavitt can be reached on (571) 272-1085. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
DR. KATIE L. PENNINGTON
Examiner
Art Unit 1634
/KATIE L PENNINGTON/Examiner, Art Unit 1634
Dr. A.M.S. Wehbé
/ANNE MARIE S WEHBE/Primary Examiner, Art Unit 1634