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 .
Application Status
The Response to the Restriction Requirement mailed on November 28, 2025 has been entered. Applicant’s election with traverse of the invention of Group II, drawn to a method of treating a subject in need of immunotherapy (claims 22-29), in the reply filed January 22, 2026 is acknowledged.
Applicant traverses “at least because a search of art relating to any one of Groups I-III will necessarily reveal the relevant art to the other groups, and vice versa”, in particular, since the Group II claims “must be practiced with the system as defined in the Group I claims”, and asserts that there would be no undue search burden to examine all of the groups together. This is not found persuasive because the method of Group II is drawn to the administration of two alternative embodiments (the synthetic signaling system of claim 1, which comprises a cell, or a nucleic acid encoding a small molecule-controlled signaling polypeptide, which does not require a cell). Furthermore, the groupings of inventions are drawn to separate statutory categories. The scope of these searches differs, rendering the search burden undue. Accordingly, the requirement is still deemed proper and is therefore made FINAL.
Claims 1-30 are pending. Claims 1-21 and 30 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Claims 22-29 are under examination herein.
Specification
The use of at least the following terms, which are a trade name or a mark used in commerce, has been noted in this application:
NANOBODY®
NANOBODIES®
DARPin®
The terms should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Objections
Claim 29 is objected to because of the following informalities: The claim appears to recite a further administration step selecting between two alternatives, but the alternatives are the same (“a soluble molecule comprising a small molecule”).
Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
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 23-29 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.
Claim 23 recites the limitation “wherein the immune cell is a T cell”. There is insufficient antecedent basis for this limitation in the claim. Claim 23 depends from claim 22, which recites “the system of claim 1” (which broadly comprises “a cell”, but does not expressly recite “an immune cell”) or “a nucleic acid encoding a small molecule-controlled signaling polypeptide” (which is not a cell).
Claim 24 recites the step of further administering a surface-attached polypeptide comprising “at least one of a small molecule acceptor peptide and a small molecule”. It is unclear from the construction of the claim whether the claim scope is intended to be drawn to:
a surface-attached polypeptide comprising (a) one or more small molecule acceptor peptides and (b) one or more small molecules, or
a surface-attached polypeptide comprising at least one of a component selected from a group of alternatives, wherein the alternatives are (a) a small molecule acceptor peptide and (b) a small molecule.
Similarly, claim 25 recites the step of further administering a polypeptide comprising “i) at least one of a small molecule acceptor peptide and a small molecule and ii) at least one of a binding domain specific for a target, an antibody, and an antibody”. With respect to i), it is unclear from the construction of the claim whether the claim scope is intended to be drawn to:
A polypeptide comprising (a) one or more small molecule acceptor peptides and (b) one or more small molecules, or
A polypeptide comprising at least one member selected from a grouping of alternatives, wherein the alternatives are (a) a small molecule acceptor peptide and (b) a small molecule.
With respect to ii), it is unclear from the construction of the claim whether the claim scope is intended to be drawn to:
A polypeptide comprising one or more of each of a binding domain specific for a target, an antibody, and an antibody reagent (For example, must a reference teach a polypeptide comprising all three of these to anticipate the instant claim?), or
A polypeptide comprising at least one member selected from a grouping of alternatives, wherein the alternatives are (a) a binding domain specific for a target, (b) an antibody, and (c) an antibody reagent.
The claimed limitations are thus ambiguous and render the intended claim scope indefinite. Given that the instant specification appears to refer to many of these limitations in the alternative by reciting “and/or” or “or” (e.g., ¶ 0007-0018; the exemplary embodiments at ¶ 0236), the Examiner will be interpreting the claims as requiring one of the listed alternatives in a given group to anticipate the claim.
Claims 26-28, which depend from claim 25, and claim 29, which depends from claim 24, do not remedy this indefiniteness and are similarly rejected.
Claim Rejections - 35 USC § 102
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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
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.
Claims 22-23 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Bradner (WO 2019/079569 A1; cited in IDS).
Bradner discloses therapeutic compositions suitable for targeted protein inactivation (e.g., Abstract). Bradner provides methods of treating a subject having a disease associated with expression of a tumor antigen that comprise administering a cell comprising a fusion polypeptide of the invention (e.g., pages 53-65), pertinent to claims 22-23. The fusion proteins described by Bradner comprise a domain that binds to a compound of Formula I, II, or III (“COF1”, “COF2”, or “COF3”, respectively)/CRBN polypeptide, which is operatively linked to a heterologous polypeptide. COF1 or COF2 corresponds to a small molecule drug such as lenalidomide or pomalidomide. (Accordingly, the COF1/CRBN-binding domain and COF2/CRBN-binding domain read on a domain that specifically binds to a small molecule.) The heterologous polypeptide is a CAR comprising a transmembrane domain and an intracellular CD3ζ signaling domain (e.g., Figure 11; pages 1-65). (As evidenced by the instant specification at page 25, CD3ζ is an exemplary “CAR stimulatory domain”.) In the presence of COF1 or COF2, the COF1 or COF2/CRBN-binding polypeptide alters the level and/or activity of the fusion protein by increasing its degradation, e.g., by a ubiquitin-dependent mechanism (e.g., pages 1-2). Bradner also discloses nucleic acid molecules encoding said fusion polypeptides as well as host cells (e.g., CAR T cells) comprising said fusion polypeptides (e.g., page 46).
Claims 22-29 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Young (US 2018/0118808 A1; cited in IDS).
Young discloses switchable chimeric receptors and use thereof in methods of treatment (e.g., Abstract). Young teaches that introduction of a switch allows for the control of CAR-T cell activity and associated immune responses, including mitigating cytokine storm (e.g., ¶ 0003-0004). Pertinent to the instantly claimed invention, Young discloses methods of treating a disease or condition (e.g., cancer) in a subject in need thereof that comprise administering a chimeric receptor-effector cell switch of the invention (e.g., ¶ 0015-0016). The switchable chimeric receptor systems of the invention comprise (1) a chimeric receptor comprising (a) a non-antibody extracellular domain that interacts with a chimeric receptor binding partner, (b) a transmembrane domain, and (c) an intracellular signaling domain (e.g., a CD3ζ stimulatory domain), and (2) a switch comprising the chimeric receptor binding partner (e.g., a small molecule) and a targeting moiety (e.g., an antibody or an antibody fragment) (e.g., Figure 2; claims 1-19, 55-56; ¶ 0005-0010), pertinent to claims 22-23 and 25. Young further provides a chimeric receptor-effector cell switch comprising (a) a chimeric receptor binding partner that interacts with a non-antibody extracellular domain of a chimeric receptor on an effector cell, and (b) a targeting moiety that interacts with a cell surface molecule (e.g., HER2 or CD19, i.e., cancer cell surface-associated markers) on a target cell (e.g., claims 57-67, 92-94; ¶ 0011), pertinent to claims 25-28. Upon binding of the antibody that interacts with a cell surface molecule, the chimeric receptor binding partner would become surface-attached, anticipating claims 24 and 29.
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 22-29 are rejected under 35 U.S.C. 103 as obvious over Lohmueller (Oncoimmunology (2018) 7(1): e1368604).
Lohmueller teaches that the creation of CARs that bind to common tag molecules (e.g., FITC or biotin, conjugated to TAA-specific antibodies) seeks to address known challenges with the application of CAR therapy, namely, antigen loss by tumors and tumor heterogeneity (e.g., Introduction). Lohmueller describes anti-tag CARs (“AT-CARs”) that bind to tags on tumor-targeting antibodies (e.g., Abstract). Lohmueller discloses, “So-called anti-tag CAR (AT-CAR) therapy would be designed so that patients are infused with a tagged, TAA-specific antibody that binds to tumor cells, followed by T cells expressing AT-CARs that react with the tagged antibodies on tumor cells (Fig. 1A). This approach has the potential to allow for sequential or simultaneous targeting of multiple tumor antigens with different antibodies. Additionally, the activity of AT-CARs can be regulated by altering the concentration of tagged antibodies or halting antibody administration for better control over potential toxicities” (Introduction, page 1).
Lohmueller generated CAR-T cells expressing an affinity-enhanced monomeric streptavidin (mAS2) protein engineered to have high affinity for biotin (i.e., a domain that binds to a small molecule), a CD28 transmembrane domain, and a CD3ζ stimulatory domain (which, as evidenced by the instant specification at page 25, is an exemplary “CAR stimulatory domain”) (e.g., pages 1-2; Figure 1), relevant to the small molecule-controlled signaling peptide administered in claims 22-23. Combination of the mSA2 CAR-T cells with a biotinylated anti-CD20 antibody (rituximab) or a biotinylated anti-CD19 antibody (FMC63) in vitro activated the CAR-T cells, inducing cytokine release and tumor lysis (e.g., pages 2-3; Figures 3-4), relevant to claims 24-29.
In contrast to the instant claims, Lohmueller does not expressly teach performing an in vivo method that comprises administering the mSA2 CAR-T cells, alone or in combination with a biotinylated anti-TAA antibody. However, Lohmueller does disclose that future experiments will include in vivo testing of mSA2 CAR-T cells with differing biotinylated antibody doses and schedules in mice bearing human tumor xenografts, thereby reading on a treatment method that comprises administering cells comprising a small molecule-controlled signaling peptide (mSA2 CAR, pertinent to claims 22-23) and a polypeptide comprising a small molecule (biotin) conjugated to an antibody against a cancer cell-specific antigen (CD19 or CD20) to a subject in need of an immunotherapy, wherein said antibody would be a surface-attached polypeptide upon binding to the surface of a cancer cell expressing the target antigen (pertinent to claims 24-29).
Accordingly, it would have been obvious to one of ordinary skill in the art, before the filing date of the instantly claimed invention, to administer a cell comprising a small molecule-controlled signaling polypeptide (i.e., the mSA2 CAR-T cell) in combination with a surface-attaching polypeptide comprising a tumor-targeting antibody (i.e., “at least one of … an antibody”, which “binds specifically to a marker on the surface of a diseased cell”, wherein “the diseased cell is a cancer cell”) that is biotinylated (i.e., comprises a small molecule) in a method of treatment for a subject in need of immunotherapy. The skilled artisan would have been motivated to do so because Lohmueller teaches that the mSA2 CAR T cells possess anti-tumor activity and are specifically activated only when the biotinylated antibody was bound to the surface of a target cell (e.g., a cancer cell) expressing the target antigen (see pages 2-3). Furthermore, Lohmueller teaches that the system can be used to potentially target many different tumor types and can be regulated by adjusting the concentration of biotinylated antibody to reduce potential toxicity (e.g., page 1). There would have been a reasonable expectation of success because it was within the skill of one of ordinary skill in the art at the time of filing to generate and to administer antibodies (with or without a synthetic tag) having specificity for a tumor-associated antigen as well as CAR constructs having specificity for a variety of antigens, including synthetic antigens such as a common tag (e.g., FITC or biotin).
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 22-29 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-23 of U.S. Patent No. 11,672,828 in view of Young (US 2018/0118808 A1; supra) or, in the alternative, Lohmueller (Oncoimmunology (2018) 7(1): e1368604; supra).
The reference patent claims a combination comprising (I) a cell or set of cells comprising one or more nucleic acids encoding a small molecule-controlled polypeptide comprising at least a first signaling domain and a polypeptide comprising a domain that binds specifically to a small molecule, and (II) a surface-attached molecule comprising a binding domain specific for a target, and a small molecule acceptor peptide (e.g., patented claims 15-18), relevant to claims 22 and 24-25.
The reference patent also claims a synthetic signaling system comprising (1) a small molecule-controlled signaling polypeptide comprising a small molecule acceptor peptide, a transmembrane domain, and a CAR stimulatory domain; (2) a polypeptide comprising a domain that binds specifically to the small molecule (e.g., biotin); and (3) a surface-attached molecule comprising a binding domain specific for a target and a small molecule acceptor peptide; and further comprising a soluble molecule comprising a small molecule (e.g., patented claims 1-14), relevant to claims 22, 24-25, and 29. Patented claims 21-23 recite a method of treating a subject in need of immunotherapy by administering an immune cell (T cell) comprising a synthetic signaling system, said system comprising (1) a small molecule-controlled signaling polypeptide comprising a small molecule acceptor peptide and at least a first signaling domain and (2) a polypeptide comprising a domain that binds specifically to a small molecule.
However, the reference patent does not teach a small molecule-controlled polypeptide comprising all three of a small molecule-binding domain, a transmembrane domain, and a CAR stimulatory domain, which is administered in a treatment method for a subject in need of immunotherapy, nor that a co-administered surface-attached molecule comprises an antibody specific for a cancer cell surface antigen.
The teachings of Young and Lohmueller, with respect to regulatable (switchable) CAR-T cell systems that may be used in methods of treating a subject in need of an immunotherapy, are discussed in the rejections under 35 U.S.C. § 102/103 above.
It would have been obvious to one of ordinary skill in the art, before the filing date of the instantly claimed invention, to modify the synthetic signaling system described in the reference patent to arrive at a cell comprising a small molecule-controlled signaling peptide comprising a polypeptide having a domain that binds to a small molecule (e.g., biotin), a transmembrane domain, and an intracellular signaling domain, wherein said small molecule-controlled signaling peptide is co-administered with a surface-attaching molecule comprising a tumor-targeting antibody and the small molecule to which the signaling peptide binds, and use of such a construct in a method of treatment. The skilled artisan would have been motivated to do so because, as demonstrated by both Young and Lohmueller, such a system would allow for administration of a disease-treating therapeutic cell (e.g., a CAR-T cell) whose activity could be modulated in vivo to minimize toxic effects. There would have been a reasonable expectation of success because it was within the skill of one of ordinary skill in the art at the time of filing to generate and to administer antibodies (alone or conjugated to a small molecule) having specificity for a tumor-associated antigen as well as CAR constructs having specificity for a variety of antigens, including small molecule-based synthetic tags (e.g., biotin).
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Elizabeth A Shupe whose telephone number is (703) 756-1420. The examiner can normally be reached Monday to Friday, 9:30am - 6:00pm EST.
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/ELIZABETH A SHUPE/Examiner, Art Unit 1643
/JULIE WU/Supervisory Patent Examiner, Art Unit 1643