DETAILED ACTION
Status of Application, Amendments and/or Claims
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
The claim listing filed on 4/27/26 has been entered. No amendments are indicated. Claims 1, 5-8, 27-29, 49-51, 71, 75, 77-79, 81, 83-84 and 87 are pending.
Election/Restrictions
Applicants' election without traverse of Invention I, claim 5, in the reply filed on 4/27/26 is acknowledged. As set forth in the restriction requirement mailed 11/26/25, claims 1, 8, 75, 77-79, 81, 83-84 and 87 are linking claims that link Inventions I-XII, and will be examined together with the elected invention. Claims 6-7, 27-29, 49-51 and 71 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.
With respect to the first requirement for an election of species, the election of “chimeric antigen receptor” as the species of “format of targeting agent” in the reply filed on 4/27/26 is acknowledged. Applicants indicate that claims 1, 5, 8, 77-79 and 81 read on the elected species. With respect to the second requirement for an election of species, Applicants argue that this requirement is “inapplicable to the elected Species I, as the therapeutic agent species … are directed to agents conjugated to or operatively linked to a targeting agent in the context of antibody-drug conjugates or similar constructs, which are distinct from the elected CAR format”. This argument is found persuasive. Claims 75, 83-84 and 87 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim.
Claims 1, 5, 8, 77-79 and 81 are under consideration, as they read upon the elected species.
Specification
The disclosure is objected to because of the following informalities:
---The title of the invention is not descriptive because it is directed generally to any method and systems for the classification and treatment of small cell lung cancer, but the claimed invention is directed to a method of treatment of small cell lung cancer using an agent targeting DLL3. A new title is required that is clearly indicative of the invention to which the claims are directed.
---The disclosure is objected to because it contains an embedded hyperlink (browser-executable code) at page X, line Y. Applicant is required to delete the embedded hyperlink; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01 (VII).
Appropriate correction is required.
Claim Objections
Claims 1, 5, 8, 77-79 and 81 are objected to for the following informalities:
Claim 1 is objected to for referencing multiple tables found in the specification. Per MPEP § 2173.05(s), "[w]here possible, claims are to be complete in themselves. Incorporation by reference to a specific figure or table ‘is permitted only in exceptional circumstances where there is no practical way to define the invention in words and where it is more concise to incorporate by reference than duplicating a drawing or table into the claims. Incorporation by reference is a necessity doctrine, not for applicant's convenience.' Ex parte Fressola, 27 USPQ2d 1608, 1609 (Bd. Pat. App. & Inter. 1993)." In the instant case, the names of the proteins listed in the tables of the specification can be written out in the claims, and thus there is a practical way to define the invention in words.
The remaining claim(s) are objected to for depending from an objected claim.
Appropriate correction is required.
Improper Markush Grouping Rejection
Claims 1, 8, 77-79 and 81 are rejected on the basis that each contains or encompasses an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984). A Markush grouping is proper if the alternatives defined by the group (i.e., alternatives from which a selection is to be made in the context of a combination or process) share a “single structural similarity” and a common use. A Markush grouping meets these requirements in two situations. First, a Markush grouping is proper if the alternatives are all members of the same recognized physical or chemical class or the same art-recognized class, and are disclosed in the specification or known in the art to be functionally equivalent and have a common use. Second, where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the alternatives do not belong to a recognized class as set forth above, the members of the Markush grouping may be considered to share a “single structural similarity” and common use where the alternatives share both a substantial structural feature and a common use that flows from the substantial structural feature. See MPEP § 706.03(y).
The elected invention under consideration is directed to use of a targeting agent capable of binding to DLL3, which is recited in dependent claim 5 (not included in this rejection), and encompassed by element (i) of independent claim 1. In this element, the recitation of “a targeting agent capable of specifically binding to one or more of the proteins of Table 1, Table 2, or Table 3” is a Markush-type grouping. However, this Markush-type grouping is improper for the following reasons. First, each of proteins listed in Tables 1-3 is a distinct polypeptide encoded by a different human gene, and the art does not recognize binding agents (e.g. antibodies) of separate proteins as belonging to the same class. Second, while the targeting agents share a common use in treatment of SCLC in the claimed method, they do not share a structural similarity. Each targeting inhibitor encompasses a genus of molecules that are structurally discrete from those of the other genus. For example, each alternative encompasses a targeting agent that is an antibody, but because each binds to a different target (e.g., DLL3, SSTR2, SEMA6D, etc), each has a different set of complementarity determining regions (CDRs) and thus does not share the same structure. The remaining claims are included in this rejection because they depend from claim 1 and encompass the same Markush type group.
To overcome this rejection, Applicant may set forth each alternative (or grouping of patentably indistinct alternatives) in a series of independent or dependent claims and/or present convincing arguments that the group members recited in the alternative within a single claim in fact share a single structural similarity as well as a common use.
Claim Rejections - 35 USC § 112(a), written description
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.-The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1, 5, 8, 77-79 and 81 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
Per MPEP 2163, 35 U.S.C. 112(a) requires, “separate and distinct from the enablement requirement”, that the “specification shall contain a written description of the invention…” (Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1355 (Fed. Cir. 2010)). In making a determination of whether the application complies with the written description requirement of 35 U.S.C. 112(a), it is necessary to understand what Applicants are claiming and what Applicants have possession of.
The instant claims are directed to a process; specifically, a method for treating a subject for small cell lung cancer (SCLC) by administration of a targeting agent. The elected invention under consideration is directed to said method, wherein the targeting agent specifically binds to the protein DLL3. This invention is encompassed by element (i) of independent claim 1, wherein the agent is administered to a subject determined to have SCLC-A. The instant specification teaches SCLC-A, which is one of “four major subtypes of SCLC”, is “defined by differential expression” of the transcription factor ASCL1 (¶ 42).
The elected species of type of targeting agent under consideration is a “chimeric antigen receptor” (CAR), which the specification teaches “are engineered receptors that combine a new specificity with an immune cell to target cancer cells”; “[t]ypically, these receptors graft the specificity of a monoclonal antibody onto a T cell, natural killer (NK) cell, or other immune cell”; and “[t]he receptors are called chimeric because they are fused of parts from different sources” (¶ 243). Thus, CARs rely on comprising the specificity of a monoclonal antibody.
The prior art recognizes that antibodies bind to epitopes of 5-7 amino acids (Benjamini et al, 1991. Immunology: A Short Course, 2nd edition, page 40 only). The human DLL3 protein has an extracellular domain of 466 amino acids (see “Recombinant Human DLL3 Protein product datasheet, Catalog #9749-2, published 10/31/22, R&D Systems by Bio-techne. No author listed, 1 page as printed, available at https://www.rndsystems.com/products/recombinant-human-dll3-protein-cf_9749-dl) Thus, even considering only continuous epitopes, the region of DLL3 expressed on the surface of tumor cells that is targeted by the CAR of the claimed method comprises many different regions of five amino acids that can serve as epitopes (e.g., residues 1-5, 2-6, 3-7, up to residues 461-466). While the general structure of an antibody was well-known in the prior art, it is the structure of the complementarity-determining regions (CDRs) that determines the specificity of a particular antibody, and said CDR structure is not predictable based on the epitope to which it binds. Thus, even knowing the structure (CDRs) of one antibody does not allow the skilled artisan to predict the structure of other antibodies that bind to the same epitope or to the other epitopes in the same protein. The relevant art, Ferrara et al (2015. mAbs. 7(1): 32-41) teaches that there is substantial variation in the structure of antibodies that bind to a single protein, on the order of hundreds of different sequences; specifically, see page 36: "The number of different HCDR3s selected against the test antigens ranges from 74 to 460 (Table 3), with the actual number of different antibodies likely to be significantly higher when different VL chains and additional VH mutations are taken into account” (pg 36). Thus, there are at least hundreds of different antibody structures that bind to the ECD of the human DLL3 protein.
Thus, the claims are genus claims because they encompass use of a genus of CARs having antibodies with the required functionality, i.e., binding to human DLL3. However, a product defined by function is not in and of itself sufficient to describe the product because it is only an indication of what the product does, rather than what it is; i.e., the specific structure of the product. It is only a definition of a useful result rather than a definition of what achieves that result. Per MPEP 2124, "describing a composition by its function alone typically will not suffice to sufficiently describe the composition". Furthermore, in the instant case the specification does not establish a correlation between structure and function; i.e., the structure of one anti-DLL3 antibody does not provide predictability regarding other antibody structures having the same functionality. Furthermore, the decision of the Federal Circuit in Amgen v. Sanofi, 872 F.3d 1367 (Fed. Circ. 2017) held that a claim directed to an antibody requires written description of the antibody itself rather than being satisfied solely by a written description of the antigen to which it binds (the so-called "newly characterized antigen" test). Thus, a description of the target protein (e.g. DLL3) is not in and of itself sufficient to provide a description of the genus of antibodies binding to said target.
Written description for a genus may also be satisfied through sufficient description of a relevant number of species. This is dependent on whether one of skill in the art would recognize necessary common attributes or features possessed by the members of the genus. Generally, in an unpredictable art, adequate description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus. Also, “[w]hen a patent claims a genus using functional language to define a desired result, the specification must demonstrate that the applicant has made a generic invention that achieves the claimed result and do so by showing that the applicant has invented species sufficient to support a claim to the functionally-defined genus" (Capon v. Eshhar, 418 F.3d 1349 (Fed. Cir. 2005)). “[A] sufficient description of a genus … requires the disclosure of either a representative number of species falling within the scope of the genus or structural features common to the members of the genus so that one of skill in the art can 'visualize or recognize' the members of the genus” (AbbVie, 759 F.3d at 1297, reiterating Eli Lilly, 119 F.3d at 1568-69).
In support of the genus of CARs binding to DLL3, the specification provides a limited number of examples of DLL3 targeting agents disclosed in the prior art, which include the antibody rovalpituzimab, the chimeric antigen receptor AMG 119 and the construct AMG 757 (¶ 63). However, mere reference to CARs or antibodies employed by the prior art is not sufficient to provide a written description of such, because it is unclear whether the sequences of such antibodies are described in the prior art, such that they can be reproducibly constructed for use in the claimed method, or are commercially available for use in the claimed method. As such, it is not considered that the specification provides a sufficient written description of any species encompassed by the claimed genus of anti-DLL3 chimeric antigen receptors. As such, the specification does not provide a representative number of species of the genus of CARs to be used in the claimed method of treatment. Furthermore, the specification does not provide any examples of other types of targeting agents capable of binding to DLL3, and thus does not provide a representative number of species of the larger genus of targeting agents binding to DLL3 to be used in the claimed method of treatment
Per MPEP 2163, "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. See AbbVie Deutschland GmbH & Co., KG v. Janssen Biotech, Inc., 759 F.3d 1285, 1300, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014) (Claims directed to a functionally defined genus of antibodies were not supported by a disclosure that "only describe[d] one type of structurally similar antibodies" that "are not representative of the full variety or scope of the genus.")
Vas-Cath Inc. v. Mahurkar, 19USPQ2d 1111 (Fed. Cir. 1991), clearly states “applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the ‘written description’ inquiry, whatever is now claimed” (pg 1117). The specification does not “clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed” (pg 1116).
For these reasons, the claims fail to meet the written description provision of 35 U.S.C. §112(a) with respect to the targeting agents capable of specifically binding to DLL3 necessary for practicing the claimed method of the elected invention. Applicants are reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. §112 is severable from its enablement provision (pg 1115).
Note on Prior Art Rejection(s)
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 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.
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.
Claims 1, 5, 8, 77-79 and 81 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Escarpe et al, U.S. Patent Application Publication 20180044415, published 2/15/18. The earliest date to which the instant application claims priority is 11/6/20.
Claims 1 and 5 each encompass a method for treating a subject for small cell lung cancer (SCLC) comprising administering a targeting agent capable specifically binding to DLL3 to a subject determined to have SCLC-A. The instant specification teaches SCLC-A, which is one of “four major subtypes of SCLC”, is “defined by differential expression” of the transcription factor ASCL1 (¶ 42). The elected species of targeting agent under consideration is a chimeric antigen receptor (CAR).
Escarpe teaches novel anti-DLL3 chimeric antigen receptors (¶ 3), for use in “treatment of lung cancer (e.g., small cell lung cancer)” (¶ 6). Escarpe further teaches that the “compositions of the invention may be used to treat tumors expressing” a marker selected from a group including ASCL1 (¶ 229), which is “known to exhibit elevated expression” in such tumors (¶ 227). As defined in the instant specification, expression of ASCL1 defines a tumor as being of the SCLC-A subtype. As such, determining that a tumor expresses ASCL1 as taught by Escarpe inherently also determines that it is of the SCLC-A subtype. As such, Escarpe teaches a method of treating a subject for SCLC comprising administering a targeting agent (i.e., a CAR) capable of specifically binding to DLL3 to a subject determined to have SCLC-A (i.e., by determining that a SCLC tumor expresses ASCL1). As such, the teachings of Escarpe anticipate claims 1 and 5.
Claim 8 encompasses a method of claim 1 wherein the subject was determined to have SCLC-A by detecting expression of ASCL1 from cancer cells in the subject. The teachings of Escarpe set forth above for claim 1 are directed to treatment of tumors expressing ASCL1. As such, the teachings of Escarpe also anticipate claim 8.
Claims 77-79 encompass a method of claim 1 wherein a cell comprising the targeting agent is administered to the subject (claim 77) and further wherein the cell is an immune cell (claim 78) that is a T cell (claim 79). Escarpe further teaches pharmaceutical compositions comprising “a population of T cells or NK cells … that express the DLL3 CAR” (¶ 206) and that a T cell expressing the DLL3 CAR is administered to a subject “to target and kill the tumor cells” (¶ 202). As such, the teachings of Escarpe also anticipate claims 77-79.
Claim 81 encompasses a method of claim 77 wherein the target agent is a CAR. The teachings of Escarpe set forth above for claim 1 (from which claim 77 depends) are directed to a targeting agent that is a CAR. As such, the teachings of Escarpe also anticipate claim 81.
Conclusion
No claims are allowable.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ZACHARY C HOWARD whose telephone number is (571)272-2877. The examiner can normally be reached on Monday to Friday from 9 AM to 5 PM. If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Vanessa Ford, can be reached at telephone number (571) 272-0857. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/ZACHARY C HOWARD/Primary Examiner, Art Unit 1674
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