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 preliminary amendment of 1/18/24 has been entered in full. Claims 3-5 and 13-16 are canceled. Claims 6, 8, 10-11 and 17 are amended. New claims 17-25 are added. Claims 1-2, 6-12 and 17-25 are pending.
Priority
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Specification
The disclosure is objected to because of the following informalities:
The title of the invention is not descriptive because it is directed in part generally to any “Use Thereof”, but the claimed methods are limited to treatment of tumors with the antibody. A new title is required that is clearly indicative of the invention to which the claims are directed. The following title is suggested: “B7-H3 Antibody and Use Thereof in Treatment of Tumors”. Appropriate correction is required.
Claim Objections
Claims 1-2, 6-12 and 17-25 are objected to because of the following informalities:
In claim 1, in lines 1-2, “wherein heavy chain complementarity determining regions” should be “wherein the heavy chain complementarity determining regions”, and in line 4, “light chain complementarity determining regions” should be “the light chain complementarity determining regions”.
In claim 2, lines 1-2, “wherein heavy chain variable regions” should be “wherein the heavy chain variable regions”, and in line 4, “light chain variable regions” should be “the light chain variable regions”.
Appropriate correction is required.
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 1-2, 6-12 and 17-25 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.
Independent claim 1 is a product; specifically, a B7-H3 antibody; i.e., an antibody that binds to the B7-H3 protein, that is defined by the sequences of its complementarity-determining regions (CDRs). Claim 2 further limits the antibody to being defined by the sequences of its heavy and light chain variable regions. Claims 6-12 and 20-25 are directed to bispecific antibodies that comprise the B7-H3 antibody of claim 1 and an anti-CD3 antibody. Claims 17 and 18 are directed to treating diseases associated with a tumor with the antibody of claim 1.
The claimed B7-H3 antibodies are limited those that comprise three heavy chain CDRs and three light chain CDRs, with each defined by reference to disclosed sequences. However, the language used with regard to these reference sequences results in the claimed antibodies failing to meet the written description requirement.
Specifically, the CDRs of the claimed antibodies are defined as “heavy chain complementarity determining regions of the B7-H3 comprise amino acid sequences as set forth in SEQ ID Nos. 6-8” and “light chain complementarity determining regions of the B7-H3 antibody comprise amino acid sequences as set forth in SEQ ID Nos. 14-16”. The language used here, i.e., “as set forth in SEQ ID NOs. 6-8”, encompasses not just sequences that encompass each of the full-length SEQ ID NO: 6, 7 and 8, but also all sequences “in” each of SEQ ID NO: 6-8, i.e., any fragment of two or more amino acids of SEQ ID NO: 6, 7 or 8. By reciting the CDRs in such a fashion, the breadth of the claims is expanded, because the antibodies encompass variants of the defined CDRs; for example, the claimed antibodies encompass those which comprise only two amino acids “as set forth in” SEQ ID NO: 6. As such the claims are directed to a genus that encompasses B7-H3 antibodies that are defined by only portions of SEQ ID NO: 6-8 and SEQ ID NO: 14-16. However, the specification does not describe which of these variants will retain the functionality of the antibody in binding to B7-H3, which is required for the antibody to be functional.
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). 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). 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 molecule (e.g. B7-H3) is not in and of itself sufficient to provide a written description of the genus of antibodies binding to said target protein.
MPEP 2163 provides guidance for complying with the written description requirement of 35 U.S.C. 112(a) that the “specification shall contain a written description of the invention…”; this requirement is separate and distinct from the enablement requirement (Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1355 (Fed. Cir. 2010)). Written description for a claimed genus may 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 written description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus. Written description for a claimed genus can also be satisfied when relevant identifying characteristics are disclosed. Per MPEP 2163, “[d]etermine whether the specification discloses other 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. For example, if the art has established a strong correlation between structure and function, one skilled in the art would be able to predict with a reasonable degree of confidence the structure of the claimed invention from a recitation of its function. Thus, the written description requirement may be satisfied through disclosure of function and minimal structure when there is a well-established correlation between structure and function.” However, claiming by function does not necessarily satisfy the written description requirement. “[A] generic statement such as "vertebrate insulin cDNA" or "mammalian insulin cDNA," without more, is not an adequate written description of the genus because it does not distinguish the claimed genus from others, except by function. It does not specifically define any of the genes that fall within its definition. It does not define any structural features commonly possessed by members of the genus that distinguish them from others … A definition by function, as we have previously indicated, does not suffice to define the genus because it is only an indication of what the gene does, rather than what it is. It is only a definition of a useful result rather than a definition of what achieves that result” (Regents of the University of California v. Eli Lilly Co., 119 F.3d 1559 (Fed. Cir. 1997)). 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).
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). As discussed above, the skilled artisan cannot envision the detailed chemical structure of the encompassed genus of anti-8-OHdG antibodies, 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. See Fiers v. Revel, 25 USPQ2d 1601 at 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016 (Fed. Cir. 1991). One cannot describe what one has not conceived. See Fiddes v. Baird, 30 USPQ2d 1481 at 1483 (BPAI 1993). In Fiddes, claims directed to mammalian FGFs were found to be unpatentable due to lack of written description for that broad class. The specification provided only the bovine sequence.
Therefore, only:
A B7-H3 antibody, wherein the heavy chain complementarity regions of the B7-H3 antibody comprising the amino acid sequences of SEQ ID NOs: 6-8, and the light chain complementarity determining regions comprise the amino acid sequences of SEQ ID NOs: 14-16, but not the full breadth of the claims meet 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).
Notes on Patentability
(1) No prior art has been identified that teaches or suggests an B7-H3 antibody that comprising the specific sets of complementarity-determining regions (CDRs) recited in the claims; specifically, heavy chain CDRs comprising the amino acid sequences of SEQ ID NO: 6-8 and light chain CDRs comprising the amino acid sequences of SEQ ID NO: 14-16.
(2) The relevant prior art recognized that B7-H3 was overexpressed in a variety of solid tumors. For example, Du et al (2019. Cancer Cell 35, 221-237) teaches that “B7-H3 is overexpressed in solid tumors but rarely in normal tissues” (page 221), further explaining that “it is aberrantly expressed in a high proportion of human malignancies” and that “[o]verexpression of B7-H3 in tumor cells frequently correlates with fewer tumor-infiltrating lymphocytes, faster cancer progression, and poor clinical outcome in several malignancies, such as pancreatic ductal adenocarcinoma (PDAC), prostate cancer, ovarian cancer (OC), lung cancer, and clear cell renal carcinoma” (page 223). Du further explains that “[d]ue to its broad expression across multiple tumor types, B7-H3 is an attractive target for cancer immunotherapy” and that “B7-H3-specific monoclonal antibodies (mAbs) and antibody-drug conjugates showed antitumor activity against B7-H3+ tumor cells in xenograft mouse models, and phase I clinical trials showed a good safety profile” (page 223).
Art of Note
The following abstract was found by the Examiner during the art search and while not relied upon for a rejection are considered pertinent to the instant application:
Li et al, 2024. Journal of Clinical Oncology. 42(16_suppl): e14509; 1 page as printed. This is a post-filing date publication as the instant application claims priority to 7/20/21. This stand-alone abstract, which includes as authors several of the inventors of the instant application, describes “EX105, a next-generation B7-H3xCD3 bispecific antibody”, which “exhibits excellent anti-tumor activity in mouse models” (page 1). Specifically, “in vivo anti-tumor activity of EX105 was further determined in several tumor xenograft models. Treatment with EX105 resulted in remarkable tumor regression in both “hot” tumor model and “cold” tumor model, indicating its effectiveness across a range of tumor types” (page 1).
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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