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 .
Restrictions/Elections
Applicant’s election of the following invention/species with traverse, as set forth in the Reply filed 16 December 2025, is acknowledged:
IA. A single pairing of three CDRs: CDR1, CDR2, and CDR3 corresponding to SEQ ID NO: 13, SEQ ID NO: 14, and SEQ ID NO: 15, respectively;
IB. A single property set forth in instant claims 7 and 10: Binding to human BCMA;
IC. A single antibody format set forth in instant claim 9, and corresponding sequence, set forth in instant claim 20: A monospecific antibody with a sequence corresponding to SEQ ID NO: 31; and
ID. A single IgG antibody subclass set forth in instant claim 19: An Fc of IgG1.
There is a search and examination burden because the claims are directed to a vast and highly varied genus of antibodies, comprising multiple different combinations of CDR1, CDR2, and CDR3 sequences, further comprising multiple different antibody formats and IgG subclasses, presumably at different dosages and dosage frequencies to achieve different end-results, namely the treatment of different diseases or conditions, wherein the route of administration may also be varied. Accordingly, from a combinatorial perspective, the claims read upon an essentially infinite variety of distinct products, which have not been identified as obvious variants on the instant record. Therefore, a full search of the scope of the claim requires, text and structure searches of all claimed antibodies and all potential substructures of all claimed antibodies in all applicable databases, with respect to all different diseases and conditions encompassed by the instant claims (e.g., PE2E, STN, REGISTRY, USGENE, A_Geneseq, Uniprot, Issued_Patents_AA, Published_Applications_AA_Main, Published_Applications_AA_New, Pending_Patents_AA_New, Pending_Patents_AA_Main, PIR_80, etc.). In addition, such searches would not find applicable dissertations, poster sessions, FDA guidance documents, NIH grant abstracts, DTIC disclosures, etc., which must be separately searched for each combination of components. In addition, there is an examination burden, because each species must be evaluated for utility (35 USC § 101), supporting description (35 USC § 112), and enablement (35 USC § 112); here, in vivo testing as presently encompassed by the claims, appears not to be reduced to practice for the majority (if not all) diseases and conditions encompassed by the claims, and therefore examination requires consideration of whether or not the limited species reduced to practice in combination with the original disclosure and prior art are sufficient to establish a structure/function relationship commensurate in scope with the presumed utility and claimed structural variability, Accordingly, in view of the vast number of combinations claimed, there is a substantial search burden if an election/restriction is not required at least because such inventions are reasonably understood to involve different fields of search and are separately classified in the art and applicable databases as explained above.. Accordingly, there is a substantial search and examination burden.
Status of the Claims
Claims 1-3, 5-11, 13, and 16-23 are currently pending and are subject to this Office Action. This is the first Office Action on the merits of the claims.
Information Disclosure Statement
The references cited on the information disclosure statement(s) were considered and have been made of record to the extent that each was provided.
Claim Rejections - 35 USC § 112(a)
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.
Claims 1-3, 5-11, 13, and 16-23 are rejected under 35 U.S.C. 112(a) 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 at the time the application was filed, had possession of the claimed invention.
Claims 1 and 2, from which claims 5-11, 13, and 16-23 depend, is drawn to an anti-BCMA single variable domain comprising 3 CDRs, wherein CDR1, CDR2, and CDR3 each have at least 70%, 85%, and 85% sequence identity with the sequences set forth in instant claim 1, respectively. As written, the present claims allow up to 64 combinations of the claimed CDR1-3 sequences with up to 25-30% variability in each sequence. The specification does not teach what amino acid substitutions are considered allowable within the sequences (i.e., specifying the preferred substitutions and at which amino acid residue(s) in each CDR sequence claimed). Moreover, the state of the art is such that even single amino acid changes can alter antigen specificity of binding, and that CDR mutations are unpredictable in terms of affinity, specificity, and solubility, and are also context dependent (see Abstract of Hall1; Abstract and Fig.3 of Vajdos2 ; Future Directions of Rabia3). Therefore, the claim contains subject matter that lacks adequate description in the specification as to reasonably convey to one skilled in the art that the inventor had possession of the full breadth of the claimed invention.
Furthermore, the present claims as written allow members within each grouping (i.e., CDR1, CDR2, and CDR3 sequence groupings) to be used interchangeably, allowing up to 64 combinations. However, the sequences within each CDR group vary significantly, e.g., CDR3 sequences set forth in SEQ ID NOs: 9 and 15 share only 14.8% sequence identity. Accordingly, the claims as written lack sufficient support that would indicate that each of the 64 combinations are operable, and lack adequate description in the specification to as to reasonably convey to one skilled in the art that the inventor had possession of the full breadth of the claimed invention.
Moreover, the decision arrived at in Amgen v. Sanofi, 872, F.3d 1367 (Fed. Cir. 2017) supports expanded analysis of whether a claim drawn to an antibody being specific for an epitope, even a specific epitope, permits an applicant to pursue all possible antibodies that are capable of being produced against such an epitope. Presently, the claimed antibody is only defined by functional properties of “binds to BCMA” and the structure of the amino acid sequences of the 3 CDRs of claim 1.
In view of the fact patterns detailed in Amgen v. Sanofi, applicants are in possession of clones 1A1, 1A10, 1A11 and 1B10, which can bind BCMA; however, “disclosure of an antigen fully characterized by its structure, formula or physical properties does not, without more, provide adequate written description of an antibody claimed by its binding affinity to that antigen” (Amgen v. Sanofi, 872, F.3d 1367 (Fed. Cir. 2017)). Applicants disclose 3 sets of 4 CDR sequences (i.e., 4 CDR1 sequences, 4 CDR2 sequences, and 4 CDR3 sequences) without variation, while the present claims allow up to 64 combinations with up to 25-30% variability in each sequence. Applicants do not identify the shared structural properties that would define the genus beyond the desired functionality; currently, the essential property of binding BCMA (including epitope specificity and binding affinities) are imparted by the three specific sets of CDR sequences that have been reduced to practice. Specifically, a description of the type and number of amino acid reside substitutions that may be made at such identified positions within the sequence would be essential in determining the degree of variability that may be allotted in total sequence identity. This lack of definition complicates the determination of the boundaries of the claimed genus with regard to which, as of yet unidentified, species variants (antibodies with CDR sequences 70-85% identical, allowing up to 25-30% variability).
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.
Claims 1, 5-11, 13, and 16-23 are rejected under 35 U.S.C. 112(b) as failing to set forth the subject matter which the inventor or a joint inventor regards as the invention.
Claims 1, 5-11, 13, and 16-23 are rejected on the judicially-created basis that it contains 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). The improper Markush grouping includes species of the claimed invention that do not share both a substantial structural feature and a common use that flows from the substantial structural feature. The members of the improper Markush grouping do not share a substantial feature and/or a common use that flows from the substantial structural feature for the following reasons:
In the present case, all of the members within each CDR grouping do not share a substantial feature or a common use that flows from the substantial structural feature. In particular, the members within the CDR3 grouping vary significantly from one another (see instant SEQ ID NOs: 12, 15, 9, and 18), e.g., see sequence alignment between instant ESQ ID NOs: 9 and 15 below:
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Furthermore, while each member within the CDR1, CDR2, and CDR3 groupings are defined by the function of binding BCMA, each CDR has not been demonstrated to bind to the same epitope of BCMA.
In response to this rejection, Applicant should either amend the claim(s) to recite only individual species or grouping of species that share a substantial structural feature as well as a common use that flows from the substantial structural feature, or present a sufficient showing that the species recited in the alternative of the claims(s) in fact share a substantial structural feature as well as a common use that flows from the substantial structural feature. This is a rejection on the merits and may be appealed to the Board of Patent Appeals and Interferences in accordance with 35 U.S.C. §134 and 37 CFR 41.31(a)(1) (emphasis provided).
Priority
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
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.
Copending Application No. 18/285,511
Claims 1-3, 5-11, 13, and 16-23 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of copending Application No. 18/285,511 (reference application; corresponding to US20240182592; effective filing date 04/15/2021). Although the claims at issue are not identical, they are not patentably distinct from each other as described below.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
MPEP § 804(II)(B)(2)-(3) identifies that a Nonstatutory Double Patenting Rejection may be appropriate based upon either an anticipation analysis or an obviousness analysis (see, e.g., MPEP § 804(II)(B)(2)-(3)). The following rejection is based upon both anticipation and obviousness analyses.
Anticipation analysis: Regarding instant claims 1-3, 5, 7-9, 17-19, and 21-23, claims 1-20 of the reference application explicitly claims antigen binding moieties comprising 3 CDRs, wherein the CDR1, CDR2, and CDR3 have the sequences set forth in SEQ ID NOs: 10-12 respectively, 13-15 respectively, or 7-9 respectively (see reference claims 1-4; compare to instant claims 1-3). The reference application further claims the antibody moieties comprising the sequences set forth in instant claim 5 (see reference claims 5-7; compare to instant claim 5); further comprising an IgG1 or IgG4 Fc region (see reference claims 11-13; compare to instant claims 17-19); as well as methods of treating the BCMA positive malignancies instantly claimed (see reference claim 20; compare to instant claims 13 and 21-23). Here, it is the Examiner’s position that under an anticipation analysis, an artisan would at once envisage the polypeptide recited in the reference claims using the exact, explicitly recited structure presently claimed (see, e.g., MPEP § 804(II)(B)(2)).
Obviousness analysis: Although the reference patent doesn’t expressly claim the limitations set forth in instant claims 6-7, 10, 16, and 20, these limitations are set forth in the reference specification. The reference application disclose the antibody moieties being derived from animals of the Camelidae family or is humanized (see reference specification bottom of p. 23 and Example 1; reads on instant claim 6); wherein the antibody moiety binds to human and/or monkey BCMA, blocks binding of APRIL to BCMA, and/or does not bind to human TACI and/or BAFFR (see reference specification at p. 12 and Examples, Example 4 in particular; reads on instant claim 7 and 10); wherein the antibody moiety is a VHH single variable domain (see reference specification Examples; reads on instant claim 16); wherein the antibody moiety comprises the sequences set forth in instant claim 20 (see reference SEQ ID NOs: 27, 29, 31, 33; compare with instant SEQ ID NOs: 27, 29, 31, 33; reads on instant claim 20). Accordingly, the present claims are directed to obvious variants4 of the claimed invention, and a skilled artisan would readily appreciate the limitations set forth in the reference patent, as the they are obvious variations described in the specification of the reference patent (see, e.g., MPEP § 804(II)(B)(1), regarding construing the claim using the reference patent disclosure).
Accordingly, instant claims 1-3, 5-11, 13, and 16-23 are not patentably distinct relative to claims 1-20 of the reference application.
Conclusion
Claims 1-3, 5-11, 13, and 16-23 are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to LEA S O'BRIEN whose telephone number is (703)756-4793. The examiner can normally be reached Monday - Friday 9:00AM - 5PM PT.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Gregory Emch can be reached on (571) 272-8149. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/LEA S O'BRIEN/Examiner, Art Unit 1646
/MARK HALVORSON/Primary Examiner, Art Unit 1646
1 Hall et al. A Single Amino Acid Mutation in CDR3 of the 3-14-9 L Chain abolished expression of the IDA 10-defined Idiotope and Antigen Binding”. Journal of immunology (Baltimore, Md. : 1950) (1992). 149 (5):1605-12.
2 Vajdos et al. “Comprehensive Functional Maps of the Antigen-binding Site of an Anti-ErbB2 Antibody Obtained with Shotgun Scanning Mutagenesis”. J Mol Biol. (2002). 320(2):415-428.
3 Rabia et al. “Understanding and overcoming trade-offs between antibody affinity, specificity, stability and solubility”. Biochemical engineering journal (2018). 137: 365-374.
4 Per MPEP § 804(II)(B)(1), it is permissible to rely on the Specification for obvious variants (see, e.g., MPEP § 804(II)(B)(1), “those portions of the specification which provide support for the reference claims may also be examined and considered when addressing the issue of whether a claim in the application defines an obvious variation of an invention claimed in the reference patent or application”).