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 amendment of 6/22/26 has been entered in full. Claims 2, 5, 12, 15-16 and 18-20 are canceled. Claims 1, 3-4, 6-11, 13-14 and 17 are amended. New claims 21-28 are added. Claims 1, 3-4, 6-11, 13-14, 17 and 21-28 are pending.
Election/Restrictions
Restriction to one of three inventive groups was required in the Office action mailed on 3/23/26: Group I corresponding to claims 1-11 and 15-17, Group II to claims 12-14 and Group III to claims 18-20. Claims 13 and 14 as amended, and new claims 21-28, are directed to the subject matter of Group I.
Applicants' election without traverse of Group I, currently all pending claims, in the reply filed on 6/22/26 is acknowledged.
Four species elections were also required. Applicants’ elections without traverse of (1) CD19 as the species of antigen; (2) SEQ ID NO: 1 as the species of TGF-β signaling modulator; (3) CD28 as the species of intracellular signaling domain; and (4) Non-Hodgkin’s lymphoma as the species of cancer, are acknowledged. The instant specification at ¶ 108 (published application) indicates that SEQ ID NO: 1 is monomeric; as such, the dimeric modulator of claim 28 does not encompass the elected species. Claim 28 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim.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, 3-4, 6-11, 13-14, 17 and 21-28 are under consideration.
Drawings
Corrected drawings in compliance with 37 CFR 1.121(d) are required because the drawings do not comply with 37 C.F.R. 1.84(U)(1), which states that partial views of a drawing which are intended to form one complete view, whether contained on one or several sheets, must be identified by the same number followed by a capital letter.
Specifically, Figures 14, 15 and 19 as filed on 8/14/23 are each presented on two sheets, labeled "FIG. X" and "FIG. X CONTINUED". The sheets should be re-labeled as parts A and B, e.g., "FIG. 14A" and "FIG. 14B".
Applicants are reminded that once the drawings are changed to meet the separate numbering requirement of 37 C.F.R. 1.84(U)(1), Applicants are required to file an amendment to change the Brief Description of the Drawings and the rest of the specification accordingly.
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). Applicants are advised to employ the services of a competent patent draftsperson outside the Office, as the USPTO no longer prepares new drawings. The corrected drawings are required in reply to the Office action to avoid abandonment of the application. The requirement for corrected drawings will not be held in abeyance.
Specification
The disclosure is objected to because of the following informalities:
---The title of the invention is not descriptive because (1) it is directed generally to any type of cell, but the claims are limited to T cells; and (2) it is directed in part to methods, but the claims are limited to products. A new title is required that is clearly indicative of the invention to which the claims are directed. The following title is suggested: “T cell Therapy Compositions for Modulating TGF-β Signaling”.
---A number of references to “TGFβ” are incorrectly presented as “TGF-b” ( ¶ 5, 8, 31-42, 48-49, 54-70, 79, 85, 87, 92, 95, 96, 100, 112, 114-120, 190, 200, 221, 377, 380, 383-384, 386, 397, 399-400, 406 and 409 of the published application) or “TGFB” (Tables 1, 2, 4 and 5; ¶ 377, 384, 387, 388, 393-394, 396, 410, 417, 421).
---Table 5 contains extraneous characters in the second column that shows the amino acid sequences. Specifically, see page 37, which has an extraneous “(SEQ ID NO: ) following four sequences and page 38, which has an extraneous “(“ following five sequences.
Appropriate correction is required.
Claim Objections
Claims 1, 3-4, 6-11, 13-14, 17 and 21-27 are objected to for the following informalities:
In claim 1, the acronym “TGFβ” should be accompanied by the full terminology the first time it appears in a series of claims, e.g., “transforming growth factor β (TGFβ)”.
In claim 8, line 1, “cells genetically engineered T” should be “genetically engineered T cells”.
In claims 23 and 27, line 2 of each, “TGFβ signaling modulator” should be “TGFβ signaling pathway modulator”. Compare with parent claims 1 and 3.
The remaining claim(s) are objected to for depending from an objected claim.
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 21 and 22 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 pre-AIA the applicant regards as the invention.
In each of claims 21 and 22, the antecedent basis of “the vector” is unclear because parent claim 9 recites “a first vector” and “a second vector” and it is unclear which one is being referred to in the dependent claim.
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, 4, 6-11, 13-14, 17, 21-22 and 27 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 claims are directed to a product; specifically, T-cells that are genetically engineered to co-express two components: (1) a chimeric antigen receptor (CAR) that recognizes a cancer antigen and comprises an amino acid sequence of any one of SEQ ID NO: 47-48, 50-57 or 62-63, and (2) a transforming growth factor β (TGFβ) signaling pathway modulator. The specification at ¶ 168 (published application) provides a definition of the term “modulator” indicates that it includes components that “positively or negatively alter an associated function”; i.e., positive regulators (activators or agonists) and negative regulators (inhibitors or antagonists). The term “expression” is defined by the specification at ¶ 157 to the product of DNA that is transcribed and translated into a polypeptide product. Thus, while the term “modulator” broadly encompasses compounds having any type of the structure, the fact that the “modulator” of the claims must be expressed by a cell indicates that is limited to a protein product (including antibodies, which are composed of one or two polypeptide chains).
The teachings of the prior art support knowledge of a genus of polypeptide-based inhibitors that function by binding to TGFβ or a TGFβ receptor; these include antibodies that bind to either of these targets as well as TGFβ receptor that bind TGFβ. See the reviews of Ciardello et al, Oct 2020. Annals of Oncology. 31(10): 1336-1349 (available on-line Jul 2020); and Lee et al, Dec 2020. J Cancer Prev 25(4): 213-222. Per MPEP 2163, with respect to written description, “What is conventional or well known to one of ordinary skill in the art need not be disclosed in detail”. The instant specification further teaches that “[p]rovided herein are TGFB signaling modulators capable of altering or preventing TGFβ receptor from signaling. A person skilled in the art would understand that this can be achieved by either binding the cytokine (i.e., TGFβ) which activates the signaling of TGFβR, or the receptor itself (e.g., a TGFβ antibody or fragment thereof, a TGFBR antibody or fragment thereof). Therefore, this term encompasses both molecules which bind TGFβ and molecules which bind TGFβR. In one embodiment, the modulator of the disclosure can neutralize TGFβ signaling through TGFβRII. By “neutralizing”, it is meant that the normal signaling effect of TGFβ is blocked such that the presence of TGFβ has a neutral effect on TGFβRII signaling” (¶ 168). As such, it is considered that claimed method possesses written description with respect to the genus of a TGF-β signaling pathway modulators that negatively alter the pathway by binding to TGFβ or a TGFβR; i.e., neutralize the activity of the signaling pathway by binding to TGFβ or a TGFβR.
However, the term “TGFβ signaling pathway modulator” also broadly encompasses polypeptides that negatively regulate the pathway by means other than binding to TGFβ or a TGFβR, or that have structures other than an antibody or TGFβ receptor, but the instant specification does not provide any examples of such, and nor are the structure of such molecules predictable from the structure of the known negative regulators that bind to TGFβ or a TGFβR.
Furthermore, as set forth above, the term “modulator” also encompasses compounds that positively regulate the TGFβ signaling pathway, and neither the prior art nor the specification provides a description of a category of TGF-β signaling pathway modulators that positively regulate the pathway; i.e., activators or agonists, other than TGF-β itself. All of the examples of modulators provided in the instant specification are directed towards negative regulation of the pathway (see the quotation above from ¶ 168 of the specification).
The claims are genus claims because they encompass use of a genus of agents with the required functionality (i.e., modulating TGFβ signaling pathway activity). No particular structure other than being a polypeptide is required, and a vast range of potential amino acid sequences are encompassed. 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 activator of TGFβ signaling (i.e., TGFβ itself) does not provide predictability regarding other agent structures having the same functionality.
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).
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.")
The specification envisions a structurally diverse genus of agents, defined solely by activity, but fails to describe with specificity a representative number of examples corresponding in scope to this genus. The specification fails to describe what changes can be made to the disclosed species to produce species having different structures and still retain the required functionality. As such, the specification fails to disclose relevant identifying characteristics sufficient to describe the claimed invention in such full, clear, concise, and exact terms that a skilled artisan would recognize applicant was in possession of the claimed invention.
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).
Therefore, only a population of genetically engineered T cells of claim 1, wherein the TGFβ signaling pathway modulator is (1) an antibody that binds to TGFβ or a TGFβR and neutralizes TGFβ signaling, or (2) a TGFβR receptor that binds to TGFβ and neutralizes TGFβ signaling, but not the full breadth of the claim meets the written description provision of 35 U.S.C. §112(a). 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.
(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.
Claims 1, 3-4, 6-11, 13-14, 17 and 21-27 are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Wyman et al, 2020/0397823, published 12/24/20, filed 6/21/19 and claiming priority to 6/21/19. The earliest date to which the instant application claims priority is Aug 15th, 2014. The earliest date to which the instant application claims priority is 2/15/21.
Claim 1 encompasses a population of genetically engineered T cells that co-express (1) a chimeric antigen receptor (CAR) that recognizes a cancer antigen and comprises an amino acid sequence SEQ ID NO: 63 (the elected species, which binds the cancer antigen CD19) and (2) a TGFβ signaling pathway modulator. The phrase “an amino acid sequence” of SEQ ID NO: 63 broadly encompasses not only the full-length amino acid sequence but also any fragment of the amino acid sequence of SEQ ID NO: 63 (this is in contrast to the phrase “the amino acid sequence” which is limited to the full-length amino acid sequence). The specification in Table 5 further teaches that SEQ ID NO: 63 is a CAR that targets human CD19 and has an CD3-1xx intracellular domain.
Wyman teaches dominant negative TGFβ receptors “for inhibiting TGF-β activity” (¶ 18). Wyman further teaches that “the DN TGF-β Receptors described herein are co-expressed in a T cell with a CAR”, including co-expression with a CAR that binds to an antigen selected from a group including CD19 (¶ 176). Wyman further provides a specific example of such an anti-CD19 CAR; specifically, “FMC63 scFv+CD28 intracellular domain+CD3ζ intracellular domain” (¶ 300). Because this CAR has a CD3 intracellular domain it shares “an amino acid sequence” with that of instant SEQ ID NO: 63. As such, the teachings of Wyman anticipate claim 1.
Claim 3 encompasses the cells of claim 1 wherein the modulator binds TGFβ. Wyman further teaches that “[i]n one aspect the polypeptide binds TGF-β1” (¶ 10). As such, the teachings of Wyman also anticipate claim 3.
Claim 4 encompasses the cells of claim 1 wherein the modulator comprises an amino acid sequence of SEQ ID NO: 1-40. The instant specification teaches, in Table 5, that SEQ ID NO: 32-40 include the extracellular domain of TGFbR1 and/or R2. The phrase “an amino acid sequence” of any one of SEQ ID NO: 32-40 broadly encompasses not only the full-length amino acid sequence but also any fragment of an amino acid sequence of SEQ ID NO: 32-40. The DN TGF-β receptors of Wyman includes those with ECDs derived from TGF-β1 or TGF-βRII (¶ 7-8). As such, these share “an amino acid sequence” with that of one or more of instant SEQ ID NO: 32-40. As such, the teachings of Wyman also anticipate claim 4.
Claims 6 and 7 encompass the cells of claim 1 that are autologous (claim 6) or allogeneic (claim 7). Wyman further teaches that the T cells of the invention may be autologous or allogeneic, e.g., at ¶ 254. As such, the teachings of Wyman also anticipate claims 6 and 7.
Claims 8 and 9 encompass the cells of claim 1 wherein the cells comprise a vector comprising nucleic acids encoding the CAR and modulator (claim 8) or two vectors comprising nucleic acids encoding such (claim 9). Wyman further teaches that host cells of the invention may be “may be transduced with one or more viral vectors comprising nucleic acid sequences encoding one or more polypeptides expressing a DN TGF-β receptor construct of the disclosure and an engineered TCR and/or a CAR” (¶ 250), which meets the limitations of claims 8 and 9 that the two components expressed by the cell are encoded by a single vector or two separate vectors. As such, the teachings of Wyman also anticipate claims 8 and 9.
Claim 10 encompasses the cells of claim 1 wherein the CAR comprises the intracellular signaling domain of CD28 (the elected species under consideration). The teachings of Wyman that anticipate parent claim 1 are directed to an embodiment wherein the CAR includes a CD28 intracellular domain. As such, these teachings also anticipate claim 10.
Claim 11 encompasses the cells of claim 1 wherein the CAR comprises a CD8 transmembrane domain. Wyman further teaches that the CARs of the invention may include a transmembrane domain selected from a group including CD8, e.g., at ¶ 150. As such, the teachings of Wyman also anticipate claim 11.
Claims 13 and 21 encompass the cells of claim 8 (claim 13) or 9 (claim 21) wherein the vector further comprises an internal ribosomal entry site (IRES). Wyman further teaches that polynucleotides of the invention may comprise “internal ribosomal entry sites (IRES)” (¶ 183). As such, the teachings of Wyman also anticipate claims 13 and 21.
Claims 14 and 22 encompass the cells of claim 8 (claim 14) or 9 (claim 22) wherein the vector further comprises a 2A self-cleaving site. Wyman further teaches that to facilitate expression of the two components in a T cell, “self-cleaving sequences may be used”, including “2A cleavable peptides” (¶ 177). As such, the teachings of Wyman also anticipate claims 14 and 22.
Claim 17 encompasses a pharmaceutical composition comprising the population of cells of claim 1. Wyman further teaches that compositions of the invention include those comprising T cells of the invention and include pharmaceutical compositions (¶ 251). As such, the teachings of Wyman also anticipate claim 17.
Claims 23-26 encompass the cells of claim 3 wherein the modulator comprises a linker (claim 23) that has the sequence of SEQ ID NO: 61, which is (GGGGS)3. Wyman further teaches that the TGFβR polypeptides of the invention may include a linker sequence; e.g., at ¶ 124. Wyman further teaches that “[illustrative examples of linkers include … glycine-serine polymers (G1-5S1-5)n, where n is an integer of at least one, two, three, four or five” (¶ 163), which is a group that includes (GGGGS)3. As such, the teachings of Wyman also anticipate claims 23-26.
Claim 27 encompasses the cells of claim 1 wherein the TGFβ signaling pathway modulator is a monomer. Wyman further teaches that polypeptides of the invention include monomeric fragments (¶ 197). As such, the teachings of Wyman also anticipate claim 27.
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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