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 .
Election/Restrictions
Applicant's election with traverse of Group I (claims 1-15 and 19) and the below listed species in the reply filed on 06/04/2026 is acknowledged.
Applicant elected Group I, drawn to multispecific antibodies that bind BCMA and T cell antigens. Within Group I, applicant elected the following species:
The first antigen-binding moiety: CDR1-3: SEQ ID NO:13-15; variable region: SEQ ID NO: 39 (corresponding to VHH: 1A11-V1);
The second antigen-binding moiety: HCDR1-3: SEQ ID NO: 43-45; LCDR1-3: SEQ ID NO: 46-48; VH/VL: SEQ ID NO: 49/50;
The third antigen-binding moiety: CDR1-3: SEQ ID NO: 10-12; variable region: SEQ ID NO: 37 (corresponding to VHH: 1A10-V1);
The orientation of the antigen-binding moieties within the multispecific antibody: The second antigen-binding moiety is an scFv, the first antigen-binding moiety, at its C-terminus, is fused to the N-terminus of one Fc polypeptide of the Fc domain, the second antigen-binding moiety, at its C-terminus, is fused to the N-terminus of the other Fc polypeptide of the Fc domain, and the third antigen-binding moiety, at its C-terminus, is fused to the N-terminus of the first antigen-binding moiety; and
Polypeptide chains: two polypeptide chains, wherein one polypeptide chain comprises an amino acid sequence set forth in SEQ ID NO: 65, and the other polypeptide chain comprises an amino acid sequence set forth in SEQ ID NO: 67.
The traversal is on the ground(s) that, as pertains to the restriction requirement, MPEP 803 requires a showing of burden on the search, wherein in the Applicant argues that the subject matter of all claims and species is sufficiently related that a thorough search for the subject matter of any one Group of claims or species would encompass a search for the subject matter of the remaining claims and species. This is not found persuasive because each invention is under a separate classification. Groups I-IV fall under C07K 2317/31, A61P 35/00, A61K 2039/505, and C07K 2317/569 respectively. Therefore, each invention has attained recognition in the art as a separate subject for inventive effort, and also a separate field of search, showing there would be a serious search and/or examination burden on the examiner if restriction is not required (see MPEP 808.02). Thus, the arguments regarding a lack of search burden are not persuasive.
The requirement is still deemed proper and is therefore made FINAL.
Claim Status
Claims 1-20 are pending. Claims 3, 5, 16-18, and 20 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. Election was made with traverse in the reply filed on 06/04/2026.
Claims 1-2, 4, 6-15, and 19, drawn to the elected group and species, are currently under consideration for patentability under 37 CFR 1.104.
Priority
This application is a 371 of PCT/CN2022/086842 (filed on 04/14/2022) which claims benefit of People’s Republic of China Application No. CN202110405638.3 (filed on 04/15/2021). Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged.
Applicant cannot rely upon the certified copy of the foreign priority application because a translation of said application has not been made of record in accordance with 37 CFR 1.55. When an English language translation of a non-English language foreign application is required, the translation must be that of the certified copy (of the foreign application as filed) submitted together with a statement that the translation of the certified copy is accurate. See MPEP §§ 215 and 216.
Because an English translation of the certified copy of the foreign priority application has not been made of the record, the examiner cannot establish whether or not what is claimed in the instant application was properly disclosed in the foreign priority application. Therefore, the benefit to the foreign priority application date is not granted.
Claims 1-2, 4, 6-15, and 19 have an effective filing date of 04/14/2022 corresponding to PCT/CN2022/086842.
Information Disclosure Statement
The information disclosure statements filed on 11/02/2023, 12/09/2024, 09/15/2025, and 06/04/2026 have been considered. Signed copies are enclosed.
Notably, the disclosure statement filed 11/02/2023 lists a Search Report. The listing of the references cited in a Search Report itself is not considered to be an information disclosure statement (IDS) complying with 37 CFR 1.98. 37 CFR 1.98(a)(2) requires a legible copy of: (1) each foreign patent; (2) each publication or that portion which caused it to be listed; (3) for each cited pending U.S. application, the application specification including claims, and any drawing of the application, or that portion of the application which caused it to be listed including any claims directed to that portion, unless the cited pending U.S. application is stored in the Image File Wrapper (IFW) system; and (4) all other information, or that portion which caused it to be listed. In addition, each IDS must include a list of all patents, publications, applications, or other information submitted for consideration by the Office (see 37 CFR 1.98(a)(1) and (b)), and MPEP § 609.04(a), subsection I. states, "the list ... must be submitted on a separate paper." Therefore, the references cited in the Search Report have not been considered. Applicant is advised that the date of submission of any item of information or any missing element(s) will be the date of submission for purposes of determining compliance with the requirements based on the time of filing the IDS, including all "statement" requirements of 37 CFR 1.97(e). See MPEP § 609.05(a).
Note: If copies of the individual references cited on the Search Report are also cited separately on the IDS (and these references have not been lined-through) they have been considered.
Claim Objections
Claim 14 is objected to because of the following informalities: “the another polypeptide chain” and “the yet another polypeptide chain” (multiple instances throughout claim) should be corrected to omit “the” from both phrases. Appropriate correction is required.
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.
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, 4, 6-8, 10-15, and 19 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.
The MPEP states that the purpose of the written description requirement is to ensure that the inventor had possession, as of the filing date of the application, of the specific subject matter later claimed. The MPEP lists factors that can be used to determine if sufficient evidence of possession has been furnished in the disclosure of the application, including “the level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention” (MPEP 2163[II][A][2]).
The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, disclosure of drawings, or by disclosure of relevant identifying characteristics, for example, structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the Applicants were in possession of the claimed genus.
(A) Claim 1 – Insufficient evidence of possession of invention regarding functional characteristics coupled with a known or disclosed correlation between function and structure
Claim 1 is drawn to “a multispecific antibody, comprising
a first antigen-binding moiety that binds to a first antigen;
a second antigen-binding moiety that binds to a second antigen; and
a third antigen-binding moiety that binds to the first antigen;
wherein the first antigen is BCMA and the second antigen is an activating T cell antigen, and the first antigen-binding moiety and the third antigen-binding moiety are both single variable domains and each independently comprise any one of:” (lines 1-7) SEQ ID NOs: 7-9, 10-12, 13-15, or 16-18 for CDR1-3.
The instant specification states “[t]he term ‘antigen-binding moiety’ refers to a polypeptide molecule specifically binding to an antigenic determinant. A specific antigen-binding moiety may be an Fab, an ScFv, or a single variable domain ” (¶ 0065, emphasis added). The use of “may” indicates this stipulation is optional. This definition includes multiple types of antigen-binding moieties, including but not limited to Fabs, scFvs, VHHs, and full-length antibodies, which have distinct structures and functions. For example, Fabs, as opposed to full-length antibodies, lack Fc constant regions; consequently, Fabs are better at penetrating tissues and have reduced immunogenicity risk (Sino Biological, Fab Antibody: Definition, Structure, and Production, 2026, Pg. 1, ¶ 2, “Antibody fragment Fab, lacking the glycosylated Fc constant regions, has the advantage over the full-length antibodies in applications requiring rapid tissue and… reducing its immunogenicity risk when used therapeutically”). This teaching by Sino Biological indicates the term “antigen-binding moiety” as recited in claim 1 encompasses a variety of distinct polypeptides (e.g. Fabs, scFvs, VHHs, and full-length antibodies). The instant specification states “four anti-BCMA/anti-CD3 multispecific antibodies disclosed herein were constructed, named BC24, PC1, PC2, and PC3” (¶ 0260, Example 9). These antibodies are trivalent and bispecific anti-CD3/anti-BCMA antibodies, wherein the CD3 binding moiety is either an scFv or Fab (Fig. 6 show configurations of trivalent and bispecific anti-CD3/anti-BCMA antibodies BC24, PC1, PC2, and PC3). Table S5 of the instant specification shows SEQ ID NOs : 43-50 for the CDR and variable region sequences for an exemplary CD3-binding moiety (¶ 0152). Therefore, Applicant fails to provide sufficient support for the entire scope of claim 1 wherein the second antigen-binding moiety encompasses a variety of distinct polypeptides. For example, the second antigen-binding moiety as recited in claim 1 can be a VHH or full-length antibody, but the instant specification fails to provide examples of such.
The instant specification states “[t]he term ‘activating T cell antigen’ refers to an antigen expressed on the surface of a T lymphocyte, such as a cytotoxic T lymphocyte, which upon interaction with an antibody is capable of inducing T cell activation” (¶ 0066) and “[t]he term ‘T cell activation’ refers to one or more cell responses of a T lymphocyte, such as a cytotoxic T lymphocyte, selected from the group consisting of proliferation, differentiation, cytokine secretion, release of cytotoxic effector molecules, cytotoxic activity, expression of activation markers, and the like” (¶ 0067, emphasis added). The use of “and the like” indicates T cell activation can occur by other means.
These definitions include a variety of antigens expressed on the surface of a T lymphocyte that induce T cell activation, wherein the molecules comprising said antigens have different downstream effects. For example, Ross and Cantrell (Signaling and Function of Interleukin-2 in T Lymphocytes, Annu Rev Immunol, 2018) teach “IL-2 [receptor] can also sustain glycolytic metabolism and other biosynthesis in cytotoxic T lymphocytes to support cell proliferation, growth, and the expression of effector molecules” (Pg. 26, Fig. 2, first ¶, last 3 lines), indicating IL-2 induces T cell activation. Additionally, Porciello and Tuosto (CD28 costimulatory signals in T lymphocyte activation: Emerging functions beyond a qualitative and quantitative support to TCR signalling, Cytokine Growth Factor Rev, 2016) teach “CD28 is one of the most important co-stimulatory receptors necessary for full T lymphocyte activation” (Pg. 11, Abstract, line 1) that “regulate[s] the expression of pro-inflammatory cytokine/chemokines” (Pg. 11, Abstract, lines 5-6). These teachings demonstrate that activating T cell molecules, like CD28 and IL-2, have distinctive downstream effects. Accordingly, the term “activating T cell antigen” encompasses numerous functionally distinct targets. As discussed earlier, the instant specification describes examples with CD3 as the activating T cell antigen (Fig. 6). Therefore, Applicant fails to provide sufficient support for the entire scope of claim 1 wherein the activating T cell antigen encompasses a variety of functionally distinct targets. For example, the activating T cell antigen as recited in claim 1 can be CD28 or IL-2, but the instant specification fails to provide examples of such.
Instead of defining the second antigen-binding moiety by its structure, the instant application uses functional characteristics, such as the ability to bind activating T cell antigens. Sevy and Meiler state “antibodies pose formidable challenges for protein structure prediction and design due to their large size and highly flexible loops in the complementarity-determining regions” (Antibodies: computer-aided prediction of structure and design of function, Microbiol Spectrum, 2014, Pg. 1 Abstract, lines 6-9). Consequently, an antibody’s structure cannot be predicted from function alone accurately.
Thus, as instantly claimed, claim 1 is drawn to a genus of trivalent and bispecific antibodies that bind BCMA and any activating T cell antigen. However, Applicant is claiming a large and structurally diverse genus of trivalent and bispecific antibodies that bind BCMA and any activating T cell antigen. Absent empirical determination, one skilled in the art would be unable to immediately envision, recognize, or distinguish at least most of the members comprised within the genus claimed, specifically (i) the identity of the activating T cell antigen and (ii) the structure of the second antigen-binding moiety that binds said antigen.
The instant specification does not sufficiently disclose a representative number of species by functional characteristics coupled with a known or disclosed correlation between function and structure. 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. As previously indicated, Applicant has disclosed 4 species within the genus claimed (i.e. trivalent and bispecific anti-CD3/anti-BCMA antibodies BC24, PC1, PC2, and PC3). However, given the large number of species encompassed by the genus claimed as well as the high level of structure variation that would be displayed by members of the claimed genus, the disclosure of 4 adequately described species is not sufficiently representative of the entire genus. Dickopf et al. state “[t]here is no ‘standard procedure’ to achieve [the generation of bispecific antibodies with desired functionalities], it rather has to be tackled on a case-by-case basis depending on the under lying biology and structural conditions” (Format and geometries matter: Structure-based design defines the functionality of bispecific antibodies, Comput Struct Biotechnol J, 2020, Pg. 1226, ¶ 6, lines 3-5). As “the design and choice of format can have a profound impact on the antibody functionality” (Dickopf et al., Pg. 1221, Abstract, lines 2-3), particularly in regard to multispecific formats, it is not possible to predict the structures encompassed in a genus of multispecific antibodies from one disclosed structure.
Furthermore, Applicant has not disclosed relevant, identifying characteristics of the second antigen-binding moiety that confer upon an antibody the ability to bind any activating T cell antigen. It is well-known in the art that antibodies generally comprise six parental CDRs. The amino acid sequences of the CDRs are hypervariable, and the amino acid residues contained within the 6 CDRs determine the antigen specificity of a particular antibody. Absent a description of at least minimal structural features correlating with a functional ability to bind activating T cell antigens which are shared by members of a genus of antibodies, it is submitted that the skilled artisan could not immediately envision, recognize, or distinguish which CDR amino acid sequences confer the ability to bind said antigens.
Although screening techniques can be used to antibodies that possess the ability to bind activating T cell antigens, Applicant is reminded that the written description requirement of 35 U.S.C. 112 is severable from the enablement provision. As stated in Vas-Cath Inc. v. Mahurkar (CA FC) 19 USPQ2d 1111, 935 F2d 1555, “The purpose of the ‘written description’ requirement is broader than to merely explain how to ‘make and use’; the applicant must also 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.”
University of California v. Eli Lilly and Co., 43 USPQ2d 1398, 1404. 1405 held that: To fulfill the written description requirement, a patent specification must describe an invention and does so in sufficient detail that one skilled in the art can clearly conclude that "the inventor invented the claimed invention.” Lockwood v. American Airlines Inc., 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (1997); In re Gosteli , 872 F.2d 1008, 1012, 10 USPQ2d 1614, 1618 (Fed. Cir. 1989) ("[T]he description must clearly allow persons of ordinary skill in the art to recognize that [the inventor] invented what is claimed."). Thus, an applicant complies with the written description requirement "by describing the invention, with all its claimed limitations, not that which makes it obvious," and by using "such descriptive means as words, structures, figures, diagrams, formulas, etc., that set forth the claimed invention" Lockwood, 107 F.3d at 1572, 41 USPQ2datl966.
Given the difficulty associated with predicting CDR combinations that yield antibodies capable of binding activating T cell antigens, and given the lack of particularity with which the genus is described in the specification, it is submitted that the skilled artisan could not immediately envision, recognize, or distinguish at least most of the members of the genus to which the claims are directed, and therefore the instant disclosure fails to demonstrate that Applicant was in possession of the claimed invention at the time the application was filed.
Accordingly, Applicant’s disclosure is not sufficient to demonstrate possession of the entire claimed antibody and Applicant’s disclosure does not satisfy the written description requirement of 35 U.S.C. 112(a).
It is noted that claim 8 teaches the activating T cell antigen is CD3, reading on a genus of trivalent and bispecific antibodies that bind BCMA and CD3, wherein the structure of CD3-binding moiety is not defined. However, as described above, absent empirical determination, one skilled in the art would be unable to immediately envision, recognize, or distinguish at least most of the members comprised within the genus claimed, specifically the structure of the CD3-binding moiety. Solely stating the identity of the antigen for the second antigen-binding moiety is not sufficient. Claim 8 does not comply with the written description requirements and is included in this rejection.
Claim 9, however, teaches the CDRs, light chain variable region, and heavy chain variable region comprising the CD3-binding moiety. This teaching is sufficient structural detail and complies with the written description requirements. Therefore, claim 9 will not be included in this rejection.
(B) Claims 6, 10, and 14 – Insufficient evidence of possession of invention regarding structure or other physical and/or chemical properties
Claim 6 is drawn to a multispecific antibody wherein the first antigen-binding moiety comprises an amino acid sequence having at least 85% identity to a sequence set forth in SEQ ID NO: 23, 39, or 40, and the third antigen-binding moiety comprises an amino acid sequence having at least 85% identity to a sequence set forth in SEQ ID NO: 21, 37, or 38.
Claim 10 is drawn to a multispecific antibody wherein the second antigen-binding moiety comprises a heavy chain variable region having an amino acid sequence having at least 85% identity to a sequence set forth in SEQ ID NO: 49 and a light chain variable region having an amino acid sequence having at least 85% identity to a sequence set forth in SEQ ID NO: 50.
Claim 14 is drawn to a multispecific antibody comprising:
two polypeptide chains, wherein one polypeptide chain comprises an amino acid sequence having at least 85% identity to a sequence set forth in SEQ ID NO: 65, and the other polypeptide chain comprises an amino acid sequence having at least 85% identity to a sequence set forth in SEQ ID NO: 67;
two polypeptide chains, wherein one polypeptide chain comprises an amino acid sequence having at least 85% identity to a sequence set forth in SEQ ID NO: 69, and the other polypeptide chain comprises an amino acid sequence having at least 85% identity to a sequence set forth in SEQ ID NO: 71;
three polypeptide chains, wherein one polypeptide chain comprises an amino acid sequence having at least 85% identity to a sequence set forth in SEQ ID NO: 59, another polypeptide chain comprises an amino acid sequence having at least 85% identity to a sequence set forth in SEQ ID NO: 61, and the yet another polypeptide chain comprises an amino acid sequence having at least 85% identity to a sequence set forth in SEQ ID NO: 63; or
three polypeptide chains, wherein one polypeptide chain comprises an amino acid sequence having at least 85% identity to a sequence set forth in SEQ ID NO: 73, another polypeptide chain comprises an amino acid sequence having at least 85% identity to a sequence set forth in SEQ ID NO: 61, and the yet another polypeptide chain comprises an amino acid sequence having at least 85% identity to a sequence set forth in SEQ ID NO: 75.
Thus, the claims include a genus of variants of the multispecific antibody in the first antigen-binding moiety (claim 6), second antigen-binding moiety (claim 10), third antigen-binding moiety (claim 6), and polypeptide chains (claim 14).
The BCMA-binding moieties tested in the instant application, applicable to the first and third antigen-binding moieties, comprise the single variable domains 1A10 (SEQ ID NO: 21), 1A10-V1 (SEQ ID NO: 37), 1A10-V2 (SEQ ID NO: 38), 1A11 (SEQ ID NO: 23), 1A11-V1 (SEQ ID NO: 39), and 1A11-V2 (SEQ ID NO: 40) (¶ 0098, Table S2, “ full-length amino acid sequences of the exemplary [BCMA-binding] single variable domains are provided in Table S2”).
The CD3-binding moiety tested in the instant application, applicable to the second antigen-binding moiety, comprises SEQ ID NOs: 49-50 for the heavy and light chain variable regions respectively (¶ 0152, Table S5, shows sequences for an exemplary CD3-binding moiety).
The instant specification states “four anti-BCMA/anti-CD3 multispecific antibodies disclosed herein were constructed, named BC24, PC1, PC2, and PC3” (¶ 0260, Example 9). These antibodies are trivalent and bispecific anti-CD3/anti-BCMA antibodies. PC1 comprises SEQ ID NOs: 65 and 67 (¶ 0262; appliable to claim 14, number 1). PC2 comprises SEQ ID NOs: 69 and 71 (¶ 0263; appliable to claim 14, number 2). BC24 comprises SEQ ID NOs: 59, 61, and 63 (¶ 0261; appliable to claim 14, number 3). PC3 comprises SEQ ID NOs: 73, 61, and 75 (¶ 0264; appliable to claim 14, number 4).
The instant specification contemplates the homologous multispecific antibodies with at least 85% sequence identities to the first antigen-binding moiety, second antigen-binding moiety, third antigen-binding moiety, and polypeptide chains as recited in the claims. However, the instant specification does not teach the three antigen-binding moieties nor the polypeptide chains modified with up to 15% amino acid substitutions and tested and remain correlated functions as wile type one. There is insufficient evidence of possession of invention regarding structure of the multispecific antibody with the variants as claimed.
Regarding claims 10 and 14, the recitation of up to 15% amino acid substitutions can occur in the VH, VL, and CDRs of the second antigen-binding moiety. Regarding claims 6 and 14, the recitation of up to 15% amino acid substitutions can occur outside of the CDRs (see base claim 1) for the first and third antigen binding moieties. Even minor changes in the amino acid sequences of the heavy and light variable regions, particularly in the CDRs, may dramatically affect antigen-binding function as evidenced by Rudikoff et al. (Proc. Natl. Acad. Sci. USA, 79(6):1979-1983, March 1982). Rudikoff et al. teach that the alteration of a single amino acid in the CDR of a phosphocholine-binding myeloma protein resulted in the loss of antigen-binding function. Colman (Research in Immunology, 145:33-36, 1994) teaches that even a very conservative substitution within the interface of the antigen-binding region of the antibody, i.e. anywhere in the VH and VL, may abolish binding or may have very little effect on the binding affinity (Pg. 35, top of left column; Pg. 33, right column). These teachings indicate amino acid substitutions both inside and outside of CDRs can completely change the antigen recognition of the antibody.
A description of a genus may be achieved by means of a recitation of a representative number of species falling within the scope of the genus or by describing structural features common the genus that “constitute a substantial portion of the genus.” See University of California v. Eli Lilly and Co., 119 F.3d 1559, 1568, 43 USPQ2d 1398, 1406 (Fed. Cir. 1997): “A description of a genus of cDNAs may be achieved by means of a recitation of a representative number of cDNA, defined by nucleotide sequence, falling within the scope of the genus or of a recitation of structural features common to the members of the genus, which features constitute a substantial portion of the genus.” The Federal Circuit has recently clarified that a DNA molecule can be adequately described without disclosing its complete structure. See Enzo Biochem, Inc. V. Gen-Probe Inc., 296 F.3d 1316, 63 USPQ2d 1609 (Fed. Cir. 2002). The Enzo court adopted the standard that the written description requirement can be met by “show[ing] that an invention is complete by disclosure of sufficiently detailed, relevant identifying characteristic, i.e., complete or partial structure, other physical and/or chemical properties, functional characteristics when coupled with a known or disclosed correlation between function and structure, or some combination of such characteristics. “ Id. At 1324, 63 USPQ2d at 1613”.
The court has since clarified that this standard applies to compounds other than cDNAs. See University of Rochester v. G.D. Searle & Co., Inc., F.3d,2004 WL 260813, at *9 (Fed.Cir.Feb. 13, 2004). The instant specification fails to provide sufficient descriptive information in the broadly claimed variants of the multispecific antibody. The specification does not provide specific or detailed structural characteristics of the variants with up to 15% amino acid substitutions in the sequences nor is clear if the functions of said variants are retained. Thus, one of skill in the art would reasonably conclude that the inventor(s), at the time the application was filed, did not have possession of the claimed invention.
MPEP § 2163.02 states, “[a]n objective standard for determining compliance with the written description requirement is, 'does the description clearly allow persons of ordinary skill in the art to recognize that he or she invented what is claimed' ”. The courts have decided: The purpose of the “written description” requirement is broader than to merely explain how to “make and use”; the 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.
As stated in the Written Description Guideline (2008), the levels of the skill and knowledge in the art would not be able to identify without further testing which of these variants could perform the same function (i.e. binding to BCMA and an activating T cell antigen, or specifically CD3) as the sequences for the multispecific antibody as recited in claims 6, 10, and 14. Based on the lack of knowledge and predictability in the art those of ordinary skill in the art would not conclude that the applicant was in possession of the claimed genus of antibody variants having the functions listed in the claims based on the limited examples given in the instant specification.
Vas-Cath Inc. v. Mahurkar, 19USPQ2d 1111, 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(s) and functional attribute(s) of the encompassed genus of variants of the antibody as claimed, 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.
One cannot describe what one has not conceived. See Fiddes v. Baird, 30 USPQ2d 1481 at 1483. In Fiddes, claims directed to mammalian FGF’s were found to be unpatentable due to lack of written description for that broad class. The specification provided only the bovine sequence.
Therefore, only the multispecific antibody comprising sequences having 100% identity to the sequences recited in claims 6, 10, and 14, but not the full breadth of the claims, meets the written description provision of 35 U.S.C. §112, first paragraph. Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. §112 is severable from its enablement provision (see page 1115).
The specification does not reasonably convey possession of the subject matter of claims 1, 6, 10, and 14. Claim 1, 6, 10, and 14 fails to comply with the written description requirement of 35 U.S.C. 112(a) as a person having ordinary skill in the art cannot reasonably conclude that the applicant had possession of the claimed invention at the time the instant application was filed. Claims 2, 4, 5-8, 11-13, 15, and 19 are included in this rejection as they incorporate and/or depend on claim 1.
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 1-2, 4, 6-15, and 19 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 applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Regarding claims 1-2, 4, 6-7, 9-10, 14, and 19, the phrase "an amino acid sequence" renders the claims indefinite because it is unclear the exact identity of the multispecific antibody as this recitation includes a large number of fragments. For claims 9-10, the second antigen-binding moiety can comprise “an amino acid sequence” of SEQ ID NOs: 43-50. As explained in the 112(a) section, the second antigen-binding moiety encompasses numerous polypeptides such as VHHs, scFvs, Fabs, and full-length antibodies; therefore, the phrase "an amino acid sequence" in claims 9-10 reads on the second antigen-binding moiety comprising amino acid fragments of SEQ ID NOs: 43-50 as well as fragments of VHHs, scFvs, Fabs, and full-length antibodies. The phrase "an amino acid sequence" should be “the amino acid sequence" to remove indefiniteness. Claims 8, 11-13, and 15 are included in this rejection as they incorporate and/or depend on claim 1.
For the purposes of claim interpretation, the phrase "an amino acid sequence" will not include amino acid sequence fragments nor antibody fragments.
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.
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Claims 1-2, 8-11, 13, and 15 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 3, 5, 7-11, 17-20, and 24-29 of copending Application No. 18/020,584 (referred to as copending ‘584) in view of US 20190367628 A1 (referred to as US ‘628; filed 2019-05-30, published 2019-12-05) as evidenced by Biointron (Role of Fab and Fc regions in Antibody Function, 2025).
Instant claims 1-2
Instant claims 1-2 teach a multispecific antibody comprising:
a first antigen-binding moiety that binds to a first antigen;
a second antigen-binding moiety that binds to a second antigen; and
a third antigen-binding moiety that binds to the first antigen;
wherein the first antigen is BCMA and the second antigen is an activating T cell antigen, and the first antigen-binding moiety and the third antigen-binding moiety are both single variable domains and each independently comprise SEQ ID NOs: 7-9, 13-15, or 16-18 for CDR1-3.
Regarding instant claims 1-2, claims 3, 5, 7-8, 10, 20, and 24-29 of copending ‘584 teach an isolated single variable binding domain or antigen-binding molecule that binds to BCMA (claim 8 of copending ‘584) or its homologs (claims 7 and 10 of copending ‘584) wherein the single variable binding domain comprises (i) SEQ ID NOs: 7-9, 13-15, or 16-18 for CDR1-3 (claims 3, 24, and 27 of copending ‘584) and (ii) SEQ ID NO: 23, 27, 31, or 33 for the VHH (claims 5, 20, 25-26, and 28-29 of copending ‘584). These SEQ ID NOs of copending ‘584 either explicitly teach or contain the CDRs of the instant application. This teaching reads on the first and third antigen-binding moieties that bind BCMA comprising instant SEQ ID NOs: 7-9, 13-15, or 16-18 for CDR1-3 (instant claims 1-2). Claim 9 of copending ‘584 teaches the isolated antigen-binding molecule is a multispecific antibody (instant claim 1).
Instant claims 11 and 13
Instant claims 11 and 13 teach the multispecific antibody comprises an Fc domain of two Fc polypeptides (instant claim 11) wherein the Fc domain is a human IgG1 or human IgG4 (instant claim 13).
Regarding instant claims 11 and 13, claims 17-19 of copending ‘584 teach the isolated antigen-binding molecule comprises a human (claim 18 of copending ‘584) immunoglobulin constant region (Fc) (claim 17 of copending ‘584), wherein the Fc is IgG1 or IgG4 (claim 19 of copending ‘584). This teaching reads on the Fc domain is a human IgG1 or human IgG4 (instant claim 13).
The claims of copending ‘584 do not explicitly state the Fc domain comprises two Fc polypeptides (instant claim 11). However, Biointron teaches a that the Fc domain “comprises the constant domains of the heavy chains” (Pg. 1, last ¶, line 1) and there are ”two identical heavy [polypeptide] chains” in an antibody (Pg. 1, ¶ 1, lines 2-3). The Fc domain of claims 17-19 of copending ‘584 inherently comprises two Fc polypeptides (instant claim 11) as evidenced by Biointron.
Instant claim 15
Instant claim 15 teaches a pharmaceutical composition comprising the multispecific antibody and a pharmaceutically acceptable carrier.
Regarding instant claim 15, claim 11 of copending ‘584 teaches a pharmaceutical composition comprising the isolated antigen-binding molecule and a pharmaceutically acceptable carrier. This teaching reads on a pharmaceutical composition comprising a protein that binds BCMA and a pharmaceutically acceptable carrier (instant claim 15).
Instant claim 8 teaches the activating T cell antigen is CD3. The claims of copending ‘584 do not teach a multispecific antibody (i) that is multivalent wherein the first and third antigen-binding moieties bind BCMA (instant claim 1) and (ii) wherein the second antigen-binding moiety binds the activating T cell antigen CD3 (instant claim 8).
US ‘628 teaches a “multispecific binding molecules… comprising a first [antigen-binding domain] ABD that specifically binds to human BCMA (“ABD1” or “BCMA ABD”) and a second ABD that specifically binds to a second antigen (“ABD2”), e.g., human CD3” (¶ 0010). US ‘628 further teaches the multispecific binding molecule “can have three ABDs (i.e., is trivalent)” (¶ 0013), wherein two ABDs bind BCMA (¶ 0127, “the trivalent [antibodies] have two ABDs that bind to one antigen [e.g., BCMA] and one ABD that binds to a different antigen”). These teachings read on a multivalent, multispecific antibody wherein the first and third antigen-binding moieties bind BCMA and the second antigen-binding moiety binds a second antigen (instant claim 1).
US ‘628 further teaches “multispecific molecules can be used to direct CD3+ effector T cells to BCMA+ sites, thereby allowing the CD3+ effector T cells to attack and lyse the BCMA+ cells and tumors” (¶ 0010) and “CD3… functions in generating activation signals in T lymphocytes” (¶ 0070), indicating that binding to CD3 on T lymphocytes leads to T cell cytotoxic activity i.e. T cell activation (see ¶ 0066-0067 of instant specification for definition of T cell activation). This teaching reads on second antigen-binding moiety binds an activating T cell antigen (instant claim 1), specifically CD3 (instant claim 8).
US ‘628 further teaches “[t]rivalent BCMA-CD3 [antibody] treatment resulted in significant anti-tumor responses” in mice (¶ 1078). This teaching provides motivation for creating a trivalent and bispecific anti-BCMA/anti-CD3 antibody for the purpose of cancer treatment.
Trivalent and bispecific anti-BCMA/anti-CD3 antibodies were known and used prior to the effective filing date of the application. In addition, both US '628 and copending ‘584 are in analogous arts (i.e. anti-BCMA antibodies, including multispecific antibodies). Since US ‘628 teaches the trivalent and bispecific anti-BCMA/anti-CD3 antibody has significant anti-tumor response and therefore useful in a method of treating cancer, there is motivation for creating a trivalent and bispecific anti-BCMA/anti-CD3 antibody as taught by US ‘628 with the specific BCMA antigen-binding moieties as taught by copending ‘584.
MPEP § 2141(III)(G) states a rationale that may support a conclusion of obviousness includes “[s]ome teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention.” MPEP § 2143(I)(G) states this rationale should explain why “[a] person of ordinary skill in the art would have been motivated to combine the prior art to achieve the claimed invention and whether there would have been a reasonable expectation of success in doing so." DyStar Textilfarben GmbH & Co. Deutschland KG v. C.H. Patrick Co., 464 F.3d 1356, 1360, 80 USPQ2d 1641, 1645 (Fed. Cir. 2006).
The teaching, suggestion, or motivation in the prior art (i.e. the trivalent and bispecific anti-BCMA/anti-CD3 antibody has significant anti-tumor response and therefore useful in a method of treating cancer as taught in US ‘628) would have led one of ordinary skill to modify the copending application (i.e. a trivalent and bispecific anti-BCMA/anti-CD3 antibody as taught by US ‘628 with the specific BCMA antigen-binding moieties as taught by copending ‘584) to arrive at the claimed invention. There is a reasonable expectation of success as trivalent and bispecific anti-BCMA/anti-CD3 antibodies were known and used prior to the effective filing date of the application. In addition, both US '628 and copending ‘584 are in analogous arts (i.e. anti-BCMA antibodies, including multispecific antibodies).
It would have been obvious to a person having ordinary skill in the art prior to the effective filing date of the instant application to use the specific BCMA antigen-binding moieties as taught by copending ‘584 in a trivalent and bispecific anti-BCMA/anti-CD3 antibody as taught by US ‘628.
Instant claims 9-10
Instant claim 9-10 teach the second antigen-binding moiety comprises SEQ ID NOs: 43-45 for HCDR1-3 and SEQ ID NOs: 46-48 for LCDR1-3 (instant claim 9) and having at least 85% sequence identity to SEQ ID NOs: 49-50 for the heavy and light chain variable regions respectively (instant claim 10).
Regarding instant claims 9-10, US ‘628 further teaches the anti-CD3 VH and VL comprises SEQ ID NOs: 267-268 respectively (Pg. 57, Table 3A, labeled as CD3-7. Instant SEQ ID NOs: 43-48 are encompassed in SEQ ID NOs: 267-268 of US ‘628. This teaching reads on the second antigen-binding moiety comprises instant SEQ ID NOs: 43-45 for HCDR1-3 and instant SEQ ID NOs: 46-48 for LCDR1-3 (instant claim 9). Instant SEQ ID NO: 49 has 93.7% sequence identity to SEQ ID NO: 267 of US ‘628. Instant SEQ ID NO: 50 has 89.3% sequence identity to SEQ ID NO: 268 of US ‘628. These teachings read on the second antigen-binding moiety having at least 85% sequence identity to instant SEQ ID NOs: 49-50 for the heavy and light chain variable regions respectively (instant claim 10).
This is a provisional nonstatutory double patenting rejection.
Claims 1-2, 4, and 6-15 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-12 and 17 of copending Application No. No. 19/394,271 (referred to as copending ‘271; reference application). Although the claims at issue are not identical, they are not patentably distinct from each other.
Instant claims 1-2 and 4
Instant claims 1-2 teach a multispecific antibody comprising:
a first antigen-binding moiety that binds to a first antigen;
a second antigen-binding moiety that binds to a second antigen; and
a third antigen-binding moiety that binds to the first antigen;
wherein the first antigen is BCMA and the second antigen is an activating T cell antigen, and the first antigen-binding moiety and the third antigen-binding moiety are both single variable domains and each independently comprise SEQ ID NOs: 10-12 or 13-15. Instant claim 4 teaches the first and third antigen-binding moieties comprise SEQ ID NOs: 13-15 and 10-12 respectively.
Regarding instant claims 1-2 and 4, claim 1 of copending ‘271 teaches a multispecific antibody comprising:
(iv) a first antigen-binding moiety that binds to a first antigen;
(v) a second antigen-binding moiety that binds to a second antigen; and
(vi) a third antigen-binding moiety that binds to the first antigen;
wherein the first antigen is BCMA and the second antigen is an activating T cell antigen, and the first antigen-binding moiety and the third antigen-binding moiety are both single variable domains and each independently comprise SEQ ID NOs: 10-12 or 13-15. SEQ ID NOs: 10-12 or 13-15 of copending ‘271 are identical to instant SEQ ID NOs of the same names (instant claims 1-2). Claim 3 of copending ‘271 teaches the first and third antigen-binding moieties comprise SEQ ID NOs: 13-15 and 10-12 respectively (instant claim 4). Claim 2 of copending ‘271 teach the first and third antigen-binding moieties comprise SEQ ID NOs: 10-12 and 13-15 respectively. The instant specification nor copending ‘271 distinguish the first and third antigen-binding moieties; therefore, they are considered identical and can be interchanged. Consequently, this teaching by claim 2 of copending ‘271 reads on the first and third antigen-binding moieties comprise SEQ ID NOs: 13-15 and 10-12 respectively (instant claim 4).
Instant claims 6-7
Instant claim 6 teaches the first antigen-binding moiety having 100% sequence identity to SEQ ID NO: 39 and the third antigen-binding moiety having 100% sequence identity to SEQ ID NO: 37. Instant claim 7 teaches (i) the first antigen-binding comprises SEQ ID NO: 39 and the third antigen-binding moiety comprises SEQ ID NO: 37 (see numbers 5 and 9) or (ii) the first antigen-binding comprises SEQ ID NO: 37 and the third antigen-binding moiety comprises SEQ ID NO: 39 (see number 10).
Regarding instant claims 6-7, claim 4 of copending ‘271 teaches the first antigen-binding comprises SEQ ID NO: 39 and the third antigen-binding moiety comprises SEQ ID NO: 37. SEQ ID NOs: 37 and 39 of copending ‘271 are identical to instant SEQ ID NOs of the same names As discussed above, the first and third antigen-binding moieties are considered interchangeable. This teaching reads on the first and third antigen-binding moieties having 100% sequence identity to SEQ ID NOs: 37 and 39 (instant claim 6) or comprising SEQ ID NOs: 37 and 39 (instant claim 7) in any arrangement.
Instant claims 8-10
Instant claims 8-9 teach the second antigen-binding domain binds the activating T cell antigen is CD3 (instant claim 8) and comprises SEQ ID NOs: 43-45 for HCDR1-3 and SEQ ID NOs: 46-48 for LCDR1-3 or SEQ ID NOs: 49-50 for the heavy and light variable regions respectively (instant claim 9). Instant claim 10 teaches the second antigen-binding domain having 100% sequence identity to SEQ ID NOs: 49-50 for the heavy and light chain variable regions respectively.
Regarding instant claims 8-10, claims 5-8 of copending ‘271 teach the second antigen-binding domains binds the activating T cell antigen is CD3 (claim 5 of copending ‘271, applicable to instant claim 8) and comprises SEQ ID NOs: 43-45 for HCDR1-3 and SEQ ID NOs: 46-48 for LCDR1-3 (claim 6 of copending ‘271, applicable to instant claim 9) or comprises SEQ ID NOs: 49-50 for the heavy and light chain variable regions respectively (claims 7-8 of copending ‘271, applicable to instant claims 9-10). SEQ ID NOs: 43-50 of copending ‘271 are identical to instant SEQ ID NOs of the same names.
Instant claims 11-13
Instant claims 11 and 13 teach the multispecific antibody comprises an Fc domain composed of two Fc polypeptides (instant claim 11) and the Fc domain is an IgG Fc domain (instant claim 13). Instant claim 12 teaches the second antigen-binding moiety is an ScFv, the first antigen-binding moiety, at its C-terminus, is fused to the N-terminus of one Fc polypeptide of the Fc domain, the second antigen-binding moiety, at its C-terminus, is fused to the N-terminus of the other Fc polypeptide of the Fc domain, and the third antigen-binding moiety, at its C-terminus, is fused to the N-terminus of the first antigen-binding moiety (see number 1).
Regarding instant claim 11, claims 9 and 11 of copending ‘271 teaches the multispecific antibody comprises an Fc domain composed of two Fc polypeptides (claim 9 of copending ‘271, applicable to instant claim 11) and the Fc domain is an IgG Fc domain (claim 11 of copending ‘271, applicable to instant claim 13). Regarding instant claim 12, claim 10 of copending ‘271 teaches the second antigen-binding moiety is an ScFv, the first antigen-binding moiety, at its C-terminus, is fused to the N-terminus of one Fc polypeptide of the Fc domain, the second antigen-binding moiety, at its C-terminus, is fused to the N-terminus of the other Fc polypeptide of the Fc domain, and the third antigen-binding moiety, at its C-terminus, is fused to the N-terminus of the first antigen-binding moiety (instant claim 12).
Instant claim 14
Instant claim 14 teaches the multispecific antibody comprises two polypeptides comprising SEQ ID NOs: 65 and 67 (see number 5).
Regarding instant claim 14, claim 17 of copending ‘271 teaches the multispecific antibody comprises two polypeptides comprising SEQ ID NOs: 65 and 67 (instant claim 14).
Instant claim 15
Instant claim 15 teaches a pharmaceutical composition comprising the multispecific antibody and a pharmaceutically acceptable carrier.
Regarding instant claim 15, claim 12 of copending ‘271 teaches a pharmaceutical composition comprising the multispecific antibody and a pharmaceutically acceptable carrier (instant claim 15).
As delineated above, claims 1-12 and 17 of copending ‘271 teach all limitations of instant claims 1-2, 4, and 6-15 regarding an anti-CD3 and anti-BCMA multispecific, trivalent antibody, rendering the instant claims obvious.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Art-Free Subject Matter
The closest prior art to claims 1-2, 4, 6-15, and 19 is US 20190367628 A1 (referred to as US ‘628; filed 2019-05-30, published 2019-12-05).
Regarding instant claim 1, US ‘628 teaches a “multispecific binding molecules… comprising a first [antigen-binding domain] ABD that specifically binds to human BCMA (“ABD1” or “BCMA ABD”) and a second ABD that specifically binds to a second antigen (“ABD2”), e.g., human CD3” (¶ 0010). US ‘628 further teaches the multispecific binding molecule “can have three ABDs (i.e., is trivalent)” (¶ 0013), wherein two ABDs bind BCMA (¶ 0127, “the trivalent [antibodies] have two ABDs that bind to one antigen [e.g., BCMA] and one ABD that binds to a different antigen”). These teachings read on a multivalent, multispecific antibody wherein the first and third antigen-binding moieties bind BCMA and the second antigen-binding moiety binds a second antigen (instant claim 1).
Regarding instant claims 1 and 8, US ‘628 further teaches “multispecific molecules can be used to direct CD3+ effector T cells to BCMA+ sites, thereby allowing the CD3+ effector T cells to attack and lyse the BCMA+ cells and tumors” (¶ 0010) and “CD3… functions in generating activation signals in T lymphocytes” (¶ 0070), indicating that binding to CD3 on T lymphocytes leads to T cell cytotoxic activity i.e. T cell activation (see ¶ 0066-0067 of instant specification for definition of T cell activation). This teaching reads on second antigen-binding moiety binds an activating T cell antigen (instant claim 1), specifically CD3 (instant claim 8).
Regarding instant claims 9-10, US ‘628 further teaches the anti-CD3 VH and VL comprises SEQ ID NOs: 267-268 respectively (Pg. 57, Table 3A, labeled as CD3-7. Instant SEQ ID NOs: 43-48 are encompassed in SEQ ID NOs: 267-268 of US ‘628. This teaching reads on the second antigen-binding moiety comprises instant SEQ ID NOs: 43-45 for HCDR1-3 and instant SEQ ID NOs: 46-48 for LCDR1-3 (instant claim 9). Instant SEQ ID NO: 49 has 93.7% sequence identity to SEQ ID NO: 267 of US ‘628. Instant SEQ ID NO: 50 has 89.3% sequence identity to SEQ ID NO: 268 of US ‘628. These teachings read on the second antigen-binding moiety having at least 85% sequence identity to instant SEQ ID NOs: 49-50 for the heavy and light chain variable regions respectively (instant claim 10).
Regarding instant claims 11 and 13, US ‘628 further teaches the antigen binding domains “can be connected to each other… by an Fc domain” (¶ 0012; instant claim 11) wherein “two Fc regions dimerize to create the Fc domain” (¶ 0085; instant claim 11) and the Fc domain can be “an IgG molecule” (¶ 0084; instant claim 13). This teaching reads on an Fc domain composes of two Fc polypeptides (instant claim 11) and the Fc domain is an IgG (instant claim 13).
Regarding instant claim 12, US ‘628 teaches “ABDs can exist as one (e.g., in the case of an scFv) polypeptide chain or form through the association of more than one polypeptide chains (e.g., in the case of a Fab)” (¶ 0060). This teaching reads on the first and third antigen-moieties being either an scFv or Fab (instant claim 12).
Regarding instant claim 15, US ‘628 teaches the BCMA binding molecules “can be formulated as pharmaceutical compositions comprising the BCMA binding molecules, for example containing one or more pharmaceutically acceptable excipients or carriers” (¶ 0660). This teaching reads on a pharmaceutical composition comprising the multispecific antibody and a pharmaceutically acceptable carrier (instant claim 15).
Regarding instant claim 19, US ‘628 teaches “Fc regions might advantageously be different to allow for heterodimerization” (¶ 0273) wherein “CH3 domains [of Fc regions] comprise modifications that favor heterodimeric association of the polypeptides” (¶ 0387). Table 6 of US ‘628 summarizes mutations that can be made to CH3 domains. This teaching reads on the Fc domain comprises an amino acid substitution that promotes association of the two Fc polypeptides of the Fc domain (instant claim 19).
US ‘628 does not teach the SEQ ID NOs for the first antigen-binding moieties, third antigen-binding moieties, and polypeptides chains (applicable to instant SEQ ID NOs: 7-18, 21, 23, 37-42, 59, 61, 63, 65, 67, 69, 71, 73, and 75) nor the arrangement of antigen-binding moieties.
It is noted that instant SEQ ID NOs: 7-18, 21, 23, 37-42, 59, 61, 63, 65, 67, 69, 71, 73, and 75 were thoroughly searched corresponding to the limitations of the claims and are free of prior art, with no sequences having 100% sequence identity to the instant SEQ ID NOs. All claims rely on unique SEQ ID NOs: 7-18 for the CDRs of the first and third antigen-binding moieties (see instant claim 1). Therefore, instant claims 1-2, 4, 6-15, and/or 19 are not anticipated by the prior are because the prior art fails to disclose each and every element of the claimed invention. In addition, instant claims 1-2, 4, 6-15, and/or 19 cannot be rendered obvious. While US ‘628 teaches a trivalent and bispecific anti-BCMA/anti-CD3 antibody, the prior art does not provide a teaching, suggestion, or motivation to modify the sequences of said antibody to arrive at the claimed invention.
Conclusion
Claims 1-20 are pending. Claims 3, 5, 16-18, and 20 are withdrawn. Claim 14 is objected to. Claims 1-2, 4, 6-15, and 19 are rejected. No claims are allowed.
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/J.M.P./Examiner, Art Unit 1642
/SAMIRA J JEAN-LOUIS/Supervisory Patent Examiner, Art Unit 1642
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