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 .
Claims 1-20, 22-23, and 34 are pending.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 34 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 34 depends from Claim 1 and comprises an amino acid sequence that is at least 80% identical to SEQ ID NO:59, or SEQ ID NO:61 or SEQ ID NO: 63. However, at least SEQ ID NO:61 does not further limit the claimed CDRs. For example, SEQ ID NO:61 appears to comprise the LCDRs and HCDRS of Claim 1(b). See below. Boxes are each CDR from left to right. Note that in claim 1(b) LCDR-1 is SEQ ID NO:31 or the 11 amino acid sequence of SASTTTSNYLN. According to claim 1, each CDR can differ by at least 80%, thus, at least nine amino acids must be identical to SEQ ID NO:31. However, as shown below the L-CDR1 of SEQ ID NO:61 appears to be SASQDISNYLN which differs by 3 amino acids and hence is less than 80% identical. Thus, claim 34 does not further limit nor include all of the limitations of the claim upon which it depends.
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Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements. Applicant should also verify that SEQ IDs 59 and 63 do not have the same issue as above.
Claims 1-20, 22-23, and 34 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. This is a written description rejection.
Claims 1-4, 10-20, 22-23, and 34 are broadly drawn to chimeric antigen receptors which lack necessary structural domains. Further, regarding claim 5 and dependents there to, the CAR of claim 5 need only comprise at least “one or more” of the necessary and essential domains. Lastly, the claimed domains of claim 5 are all generic to large number of variant domains inclusive of hinge regions, signal peptides, transmembrane domains, co-stimulatory regions, and cytoplasmic signaling domains. Generally, a genus can be sufficiently disclosed by 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. “A written description of an invention involving a chemical genus, like a description of a chemical species, ‘requires a precise definition, such as by structure, formula, [or] chemical name,’ of the claimed subject matter sufficient to distinguish it from other materials.” Regents of the Univ. of Cal. v. Eli Lilly & Co., 119 F.3d 1559, 1568 (Fed. Cir. 1997) (quoting Fiers v. Revel, 984 F.2d 1164, 1171 (Fed. Cir. 1993)).
For example, the CAR does not function without its respective components. Abate-Daga et al. (Molecular Therapy — Oncolytics (2016) 3, 16014) teach (page 1, 2nd column) that the CAR is a hybrid antigen receptor, part antibody and part TCR, and is composed of an extracellular antigen-binding domain and intracellular signaling domain(s). Further, the hinge, spacer, and transmembrane domains connect the scFv to the activation domains and anchor the CAR in the T-cell membrane. Recent studies have demonstrated that these domains can have significant impact on CAR T-cell function and can be optimized to enhance antigen binding and T-cell signaling (page 3, 2nd column). Also, as of 2016, all CARs currently tested in the clinic contained either CD28, 4-1BB (CD137) or a combination thereof as CD28 costimulation enhances survival of CAR-T cells in patients (page 4, 1st column).
Regarding transmembrane domains, the specification discloses [0024] that the transmembrane domain may comprise or be a variant of a transmembrane domain of CD8, CD28, CD3, CD45, CD4, CD5, CD9, CD16, CD22, CD33, CD37, CD64, CD80, CD86, CD134, CD137, CD154, or combinations thereof. Thus, the included structures are relatively undefined and remain generic. Moreover, the CARs of claims 1-4, 10-20, 22-23, and 34 do not even define nor require the presence of a transmembrane domain. Here, it is noted that no one element of the conventional CAR, typically comprising an extracellular ligand binding domain, a spacer, a transmembrane domain, and an intracellular (cytoplasmic) signaling domain, has been found to be purely structural. Even the transmembrane domain, which might at once been regarded to have played only a structural role, has been found to impart particular functional properties upon the CAR. Bridgeman et al. (J. Immunol. 2010 Jun 15; 184 (12): 6938-49) found, for example, that CARs containing the CD3ζ transmembrane domain can form a complex with the endogenous TCR that may be beneficial for optimal T cell activation, a property that could be abolished by altering the structure of the transmembrane domain by amino acid substitution (see entire document; e.g., the abstract). It is therefore reasonable to question whether a CAR which might comprise any given “transmembrane domain” or any given “cytoplasmic signaling domain” will function as intended.
Moreover, all of the claims can have as much as 20% variability in the CDR regions or in the entire VH or VL regions and applicants are not in possession of the genus of variant CDRs or VH/VL domains. However, the instant specification fails to provide sufficient descriptive information, such as definitive structural or functional features of the claimed genus of antigen binding domains that would distinguish the claimed CAR requirements from other molecules that do not have the claimed biological properties. Since the disclosure fails to describe the common attributes or characteristics that identify members of the genus, and because the genus is highly variant, the disclosure of 80% variability to a genus of anti-BCMA binding regions is insufficient to describe the large genus. In this case, a recitation of “percent identity” does not limit the differences in amino acid sequence to residues outside the CDRs. And while it is possible to screen for variants that retain antigen binding, it is respectfully submitted that the number of possible substitutions permitted by “percent identity” language does not allow the skilled artisan to envisage those variants not yet made which would retain the required function. The heavy chain variable region section alone recited in the instant claim 3 (SEQ ID NO:2, 4, or 6) is about 100 amino acids. If one amino acid is substituted by each of the other 19 amino acids in a polypeptide with 100 residues, there are 1,900 variant polypeptides. Substituting 20 amino acids (i.e., 20% identity) results in approximately 190020 variant polypeptides, or over 1065 variants for a single variable region. The ability of the claimed CAR to bind to its antigen is an essential feature of the claimed invention; therefore, the skilled artisan would need to identify functional variants of the antibody in order to make and use the invention. The diversity of polypeptide libraries that can be screened by present-day high-throughput methods is generally assumed to be about 109, or one billion variants. E.g., Rentero et al., Chimia, 65: 843-845 (2011); see entire document, in particular e.g. the first sentence of the Introduction at page 843). Thus, one of skill in the art would reasonably conclude that the disclosure fails to provide a representative number of species to describe and enable the genus as broadly claimed.
Further, as of the effective filing date, and regarding methods of treating cancer, the claims encompass any and all cancers (Claim 14) or any cancer that is BCMA-positive (Claim 17). The claims also encompass any hematological or plasma cell malignancy. This encompasses a huge genus of highly diverse types of cancer. However, the only method that the claims particularly function towards appears to be multiple myeloma (Specification, Example 12). Further, the state of the art at the effective filing date does not provide evidence that anti-BCMA CAR-T directed therapy is functional in a variety of different cancers. For example, Munshi et al. (May 2020, Applicant’s IDS) teach that Ide-cel, a BCMA targeted Car-T cell therapy showed promising tolerability and efficacy in multiple myeloma patients. Along these lines, Feng et al, (May 2020, Applicant’s IDS) teach (page 110) that CD19 targeted CAR-T cells achieved good results in in acute lymphoblastic leukemia, chronic lymphocytic leukemia, and non-Hodkgins’s lymphoma. At the same time, the treatment for multiple myeloma and relapsed/refractory multiple myeloma (RRMM) with CAR-T cell is still underway. The authors teach that BCMA is mainly expressed on terminally differentiated normal B cells and plasmablasts and also expressed on all multiple myeloma cells in most patients. Table one provides a summary of clinical trials of anti-BCMA CAR-T products with the only indication of treating multiple myeloma or RRMM and no other tumors.
Vas-Cath, Inc. v. Mahurkar, 935 F.2d 1555, 1563-64, 19 USPQ2d 1111, 1117 (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.” (See page 1117.) The specification does not “clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed.” (See Vas-Cath at page 1116). As discussed above, the skilled artisan cannot envision the detailed chemical structure of the encompassed genus of variant CAR polypeptides, and therefore conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method of isolation. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method of isolating it. The compound itself is required.
For inventions in an unpredictable art, adequate written description of a genus, which embraces widely variant species cannot be achieved by disclosing only several species within the genus. In the instant case, applicant has disclosed some structural features of exemplary CARs and one particular treatment for multiple myeloma, but this does not compensate for the huge genus as set forth in Claim 1 and 14. While it is true that some transmembrane domains, signal domains, hinge regions, etc. were known, the disclosure demonstrates that, for even the narrowest claims at issue, the realm of such possible structural domains is vast. Without this necessary structural guidance, the above claims do not satisfy the written description requirement.
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.
Claim(s) 1-20, 22-23 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by WO 2019/196713 (Wei et al., published 10/17/2019, IDS.)
As to claims 1 and 3, Wei et al. teach chimeric antigen receptors with 100% identity to SEQ ID NO:1 containing LCDR1 (SEQ ID NO:17), LCDR2 (SEQ ID NO:19), and LCDR3 (SEQ ID NO:21). Qy=applicant’s SEQ D NO:1, and Db=Wei’s SEQ ID NO:1 (page one of Wei’s sequence listing). Boxed regions are CDRs 1-3, from left to right.
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Below, Wei et al. teach 100% identity to SEQ ID NO:2 containing HCDR1 (SEQ ID NO:24), HCDR2 (SEQ ID NO:26), and HCDR3 (SEQ ID NO:28). Qy=applicant’s SEQ D NO:2, and Db=Wei’s SEQ ID NO:2 (page two of Wei’s sequence listing).
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Below, Wei et al. teach 100% identity to SEQ ID NO:3 containing LCDR1 (SEQ ID NO:31), LCDR2 (SEQ ID NO:33), and LCDR3 (SEQ ID NO:35). Qy=applicant’s SEQ D NO:3, and Db=Wei’s SEQ ID NO:3 (page three of Wei’s sequence listing).
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Below, Wei et al. teach 100% identity to SEQ ID NO:4 containing HCDR1 (SEQ ID NO:38), HCDR2 (SEQ ID NO:40), and HCDR3 (SEQ ID NO:42). Qy=applicant’s SEQ D NO:4, and Db=Wei’s SEQ ID NO:4 (pages 3-4 of Wei’s sequence listing).
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Below, Wei et al. teach 100% identity to SEQ ID NO:5 containing LCDR1 (SEQ ID NO:45), LCDR2 (SEQ ID NO:47), and LCDR3 (SEQ ID NO:49). Qy=applicant’s SEQ D NO:5, and Db=Wei’s SEQ ID NO:5 (pages 4-5 of Wei’s sequence listing).
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Below, Wei et al. teach 100% identity to SEQ ID NO:6 containing HCDR1 (SEQ ID NO:52), HCDR2 (SEQ ID NO:54), and HCDR3 (SEQ ID NO:56). Qy=applicant’s SEQ D NO:6, and Db=Wei’s SEQ ID NO:6 (pages 5-6 of Wei’s sequence listing).
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As to clam 2, Wei et al. teach (page 3, and claims of Wei) that the above VL regions are “located at the N-terminus of VH”.
As to claim 4, Wei et al. teach (page 12) that the anti-BCMA antigen-binding region can be a single-chain variable fragment (scFv).
As to claims 5-9, Wei et al. teach (page 6) that the structure of the CAR further comprises one or more of a signal peptide, a hinge region, a transmembrane domain, a co-stimulatory region, and a cytoplasmic signaling domain. The co-stimulatory domain can comprise a co- stimulatory region of OX40, CD2, CD7, CD27, CD28, CD30, CD40, CD70, CD134,4-1BB (CD137), PD1, Dap10, CDS, ICAM-1, LFA-1 (CD11a/CD18), ICOS (CD278), 35 NKG2D, GITR, TLR2, or a combination thereof. The cytoplasmic signaling domain comprises a cytoplasmic signaling domain of CD3ζ. The hinge region comprises a hinge region of CD8, CD28, GM-CSF, CD4, CD137, or a combination thereof. The reference further teaches that the transmembrane domain can comprise a region of a protein selected from the group consisting of CD28, CD3c, CD45, CD4, CD5, CD8, CD9, CD16, CD22, CD33, CD37, CD64, CD80, CD86, CD134, CD137, CD154, or a combination thereof.
As to claims 10-13, Wei et al., teach (page 14) that the chimeric antigen receptor is expressed in a T-cell and that nucleic acid sequences coding for the desired molecules can be obtained using recombinant methods known in the art, such as, for example by screening libraries from cells expressing the gene, by deriving the gene from a vector known to include the same, or by isolating directly from cells and tissues containing the same, using standard techniques. Further, the reference teaches that the invention also provides vectors in which the expression cassette of the present invention is inserted.
As to claims 14-20, and 22-23, the reference teaches (abstract and page 18) a method of treating cancer including hematologic cancers such as a multiple myeloma (a plasma cell malignancy which can also develop into an aggressive form of “plasma cell leukemia”). The reference further teaches that the CAR mediated immune response may be part of an adoptive immunotherapy approach in which CAR-modified T cells induce an immune response specific to the antigen binding moiety in the CAR. For example, an anti-BCMA CAR-T cell elicits an immune response specific against cells expressing BCMA (this would encompass a BCMA-positive malignancy). Additionally, the abstract specifically teaches: “The CAR of the present invention targets BCMA-positive cells, and can be used for treating diseases such as BCMA-positive B cell lymphoma, multiple myeloma, and plasma cell leukemia.”. The reference further teaches (See page 27, and Wei’s claims 10-14) that the T cell is administered by infusion, injection, transfusion, implantation, and/or transplantation and can be administered intravenously, subcutaneously, intradermally, intranodally, intratumorally, intramedullary, intramuscularly, or intraperitoneally. Further, the T cell can be allogeneic or autologous and that the subject is a human.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-20, and 22-23 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-4 of U.S. Patent No. 11498973. Although the claims at issue are not identical, they are not patentably distinct from each other.
Claims 1-4 of US Patent 11498973 are drawn to chimeric antigen receptors comprising an overlapping structure of the currently claimed anti-BCMA antigen binding regions and pharmaceutical compositions thereof:
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In the instant case, the pending claims are drawn to the same VH (SEQ ID NO:2) and VL (SEQ ID NO:1) regions as currently patented. The pending specification also includes all of the claimed sequences for other structural aspects (hinge, transmembrane region, co-stimulatory region, etc). Further, it would be obvious to use the patented CAR to treat cancers that are BCMA-positive or of hematological origin.
Claims 1-20, and 22-23 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-7 of U.S. Patent No. 11142581. Although the claims at issue are not identical, they are not patentably distinct from each other.
Claims 1-7 of US Patent 11142581 are drawn to methods of treating multiple myeloma associated with expression of BCMA comprising administering chimeric antigen receptors comprising a species of anti-BCMA antigen binding regions and pharmaceutical compositions thereof:
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The pending claims are drawn to administering the same VH (SEQ ID NO:2) and VL (SEQ ID NO:1) regions expressed in T-cells as currently patented. The pending specification also includes all of the claimed sequences for other structural aspects (hinge, transmembrane region, co-stimulatory region, etc).
Claims 1-20, and 22-23 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-5 of copending Application No. 17/951774 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
The claims of the reference application are drawn to nucleic acids, vectors, engineered T-cells and pharmaceutical compositions all comprising the same VL and VH regions of the anti-BCMA antibody as claimed in the currently pending application. The pending specification also includes all of the claimed sequences for other structural aspects (hinge, transmembrane region, co-stimulatory region, etc). Further, it would be obvious to use the reference CAR to treat cancers that are BCMA-positive or of hematological origin.
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to GARY B NICKOL, Ph.D. whose telephone number is (571)272-0835. The examiner can normally be reached M-F 9AM-5:30PM.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Julie Wu can be reached at 571-272-5205. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/GARY B NICKOL/Primary Examiner, Art Unit 1643