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 of species of antibody for which the target antigen is DLL3 and which comprises SEQ ID NO:73 (VH), 74 (VL), 75 (binding domain) and 76 or 77 (bispecific antibody constructs) in the reply filed on 11/18/2025 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Specification
The title of the invention is not descriptive. A new title is required that is clearly indicative of the invention to which the claims are directed.
The following title is suggested: Bispecific Antibody Pharmaceutical Formulation
The disclosure is objected to because of the following informalities: In [0002] the name and size of the sequence listing are incorrect. Please refer to the Electronic Acknowledgement Receipt mailed 10/07/2022, the pertinent part of which is reproduced below:
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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 22 and 26 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.
Claims 22 and 26 directly depend from independent claim 1, which is drawn to an aqueous pharmaceutical formulation comprising (a) a bispecific antibody construct, (b) a saccharide, (c) a surfactant, and (d) a buffer, wherein the pH is from about 4.8 to about 5.5. There are no specific species of (a)-(d) recited in claim 1, 22 or 26. Claim 22 further limits the formulation as comprising less than 10% of low molecule weight (LMW) clipping product [fragments] of the bispecific antibody construct after storage at 40˚C for one month. Claim 26 further limits the formulation as comprising less than 5% of high molecule weight (HMW) aggregates of the bispecific antibody construct after storage at 40˚C for one month. However, the specification only discloses obtaining these results for LMW clipping products or HMW aggregates of the bispecific antibody construct after storage at 40˚C for one month for the construct which is a BiTE® (bispecific T cell engaging) antibody defined as “a fusion protein consisting of two single-chain variable fragments (scFvs) joined by a linker” construct, which is a single chain antibody comprising a first and second binding domains, each comprising a variable heavy chain region (VH) and a variable light chain region (VL), and a third domain comprising, in an amino to carboxyl order, hinge-CH2 domain-CH3 domain-linker-hinge-CH2 domain-CH3 domain ([0069] and [0016], claims 13-15). The specification provides no description of the different BiTE® antibody constructs (-I, -C, -D, -G) used in the Examples.
Achieving a formulation wherein LMW clipping product is less than 10% at 40˚C after one month (claim 22) was only obtained when the BiTE®-containing liquid formulation consisted of ([0148]): 1 mg/mL BiTE molecule, 10 mM L-glutamic acid, 9% (w/v) sucrose and 0.01% (w/v) polysorbate 80, at a pH of 4.2-5.2 (Example 1). Interestingly, using only the particular bispecific antibody construct, BiTE®-G, the formulation at pH 4.8 not pH 4.2 led to % LMW less than 10% at 40˚C for one month (Example 4, Table 2 and Fig. 2), which appears to be different than the results obtained in Example 1 (Table 1 and Fig. 1). The results of Examples 1 and 4 are inconsistent with those of Example 6 for BiTE®-G in the same formulation at pH 4.8 or 5.2 (Formulations B and C of Table 3), which at 40˚C had a % LMW of 15.4 and 14.3%. The same formulation at pH 3.8 had 28% LMW. Two other formulations, one with acetate buffer at pH 5.2 and one with phosphate buffer at pH 7.4 had respectively, 15.1 and 40.0% LMW (Table 3 and Fig. 3A). Consistent with BiTE®-G results, when BiTE®-D was instead used in these formulations with storage at 40˚C for one month, none of the formulations had a % LMW less than 10% (Table 4 and Fig. 3B). As a result, there is no written description for any non-BiTE® antibody construct meeting the % LMW clipping product at the required temperature and storage duration and the conflicting results in the specification for % LMW under apparently the same conditions for the same antibody constructs makes the data hard to interpret.
To obtain a HMW aggregation of less than 5% for a bispecific construct at 40˚C after one month (claim 26), the same six conditions used in Example 6 for determining % LMW were used with BiTE®-G and -D. For % HMW, all BiTE®-G- or -D-containing formulations (glutamate and acetate buffer at the specified pHs) except the phosphate buffered, pH7.4, met the limitations of claim 26 (Tables 5 and 6). Unfortunately, these results do not distinguish whether the phosphate buffer or the higher pH was responsible for the failure of that group, despite the specification saying otherwise ([0167]). The correct comparison would have been a second acetate buffer formulation at pH 7.4 and/or second phosphate buffer formulation at pH 5.2. That the required % HMW could be obtained with a glutamate and acetate buffer formulation that was otherwise identical, does not mean i) that changing the other components of the formula would yield the same results or ii) that using a buffer beside glutamate or acetate would yield the same results. Additionally, only one formulation with a pH higher than 5.2 was tested, and this was the phosphate buffer-containing formulation, which did not meet the limitations of either claim 22 or 26 (E of Example 6).
Kang et al. (https//bioprocessintl.com/manufacturing/formulation/rapid-formulation-development-formonoclonal-antibodies/, April 2016) shows that antibody formulation is empirical, with each antibody having potentially different optimized conditions, from pH to buffer to surfactant to saccharide or polyol (esp. pp. 2-3/7). Wang et al. (Int’l J. Pharmaceutics, 568:118505, 24 pages, 2019, Table 1 and section 2.2.1, 2.3.3 and 2.3.4) teaches that protein stability in solution, including antibody stability, is influenced by factors including formulation, process, temperature and light, with formulation factors including pH, ionic strength, excipients and contaminants, which contribute to colloidal stability, chemical degradation, aggregation and/or fragmentation. Not only do different excipients and buffers affect protein stability, but their concentration also is a variable. So too is the concentration of the therapeutic protein in solution (section 2.3.5). As stated in section 3. “Art of protein formulation development: The sensitivity and unpredictability of protein stability requires significant efforts in finding an optimal formulation condition/composition to maximize stability for different manufacturing steps and longterm storage. This exploratory and experimental process is formulation development.”
Vas-Cath Inc. v. Mahurkar, 19USPQ2d 1111 (Fed. Cir. 1991), clearly states that “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).
At the most for claim 26, it reasonably appears that only a bispecific antibody construct which is a BiTE® and a formulation therewith consisting of 1 mg/mL BiTE® molecule, 10 mM L-glutamic acid or acetate, 9% (w/v) sucrose and 0.01% (w/v) polysorbate 80, at a pH of 4.2-5.2, meets the written description provision of 35 U.S.C. § 112(a), but not the full breadth of the claim, i.e., other bispecific antibody construct formats or other buffers, saccharides, surfactants or concentrations or pHs. Further, the description supports the amounts/concentrations of each component as described in the above formulation or commensurately higher or lower amounts consistent with the entire formulation. For claim 22, it is unclear if any of the formulations meet the written description provision of 35 U.S.C. § 112(a) for the claim limitations in view of the results shown in Tables 3 and 4 after storage at 40˚C after one month, none of which showed less than 10% LMW clipping product of the bispecific antibody construct). 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).
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1, 2, 5, 7, 10-15, 22 and 26 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2, 24 and 28 of copending Application No. 16/482,603* (‘603, reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because both claim a liquid (aqueous) formulation of a bispecific antibody construct (claim 1 of each), comprising a buffer, e.g., glutamate, a saccharide, e.g., sucrose, a surfactant, e.g., polysorbate 80, and having a pH from about 4.8 to 5.5 (instant claim 1) or 4.0 to 5.0 (claim 1 of ‘603), which pH ranges overlap, and wherein one binding domain binds CD3 and the other binds DLL3, and the antibody construct comprises a hinge, CH2 and CH3 domain (claim 1 of ‘603, and instant claims 2, 5, 7, 10, 12, 13 and 16). The construct may be or comprise a single chain antibody construct (claim 2 of ‘603 and instant claims 14-15). The antibody construct is in a concentration of 0.1-8 mg/ml (claim 28 of ‘603 and instant claim 11). The concentration of low molecule weight (LMW) clipping product and high molecule weight (HMW) aggregates are inherent to the formulation and storage conditions (instant claims 22 and 26).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
*N.b. This application has been allowed, so when it issues as patent the rejection will convert to a non-provisional rejection.
Claims 1, 5, 7, 10-12, 14, 15, 22 and 26 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 38, 43, 46, 62 and 64-68 of copending Application No. 16/964,452 (‘452, reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because both claim a liquid (aqueous) formulation of a bispecific antibody construct (claim 1 of each). In the case of ‘452, the bispecific antibody construct is trivalent, which does not affect it being bispecific. Both constructs bind CD3 and comprise a variable heavy and light chain (VH and VL, respectively), e.g. from a Fab or scFv (claim 1 of ‘452 and instant claims 14-15). The formulations of both comprise a buffer, e.g., glutamate, a surfactant, e.g., polysorbate 80, and sucrose (claim 1 of ‘452 and instant claims 1, 5, 7 and 10, including wherein the antibody construct concentration is from 0.1-20 mg/ml (claims 65-68 of ‘452 and instant claim 11). The polyol of claim 62 of ‘452 includes sucrose and sorbitol (instant claim 5, see definition in [0098] of ‘452). Because claim 1 recites the pH as “from about 4.8 to about 5.5”, this encompasses a pH of 4.2 to 4.6 of ‘452 because the instant specification defines “about” as meaning “the recited number plus or minus 5%, 10%, 15% or more of that recited number.” ([0048]) The specification in [0047] says, “For example, "a pH from about pH 4.8 to about pH 5.5," could be, but is not limited to, pH 4.6, 5.2, 5.5 etc….” Therefore, the pH ranges of the formulation for each application overlap. The concentration of low molecule weight (LMW) clipping product and high molecule weight (HMW) aggregates are inherent to the formulation and storage conditions (instant claims 22 and 26).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1, 2, 5, 7, 10-12, 14, 15, 22 and 26 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2, 24 and 28 of copending Application No. 17/262,962 (‘962, reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because both claim a liquid (aqueous) formulation of a bispecific antibody construct (claim 1 of each), comprising a buffer, e.g., glutamate, a saccharide, e.g., sucrose, a surfactant, e.g., polysorbate 80, and having a pH from about 4.8 to 5.5 (instant claim 1, 5, 7, 10) or about 4.2 (claim 1 of ‘962), which overlap in view of the definition in the instant specification of “about” as meaning “the recited number plus or minus 5%, 10%, 15% or more of that recited number.” ([0048]) Both claim wherein a binding domain binds CD3 and either binding domain comprises a scFv or Fab (claims 1, 4, 40 of ‘962, and instant claims 12, 14, 15). The antibody construct is in a concentration of 0.1-20 mg/ml (claim 28 of ‘962 and instant claim 11). The concentration of low molecule weight (LMW) clipping product and high molecule weight (HMW) aggregates are inherent to the formulation and storage conditions (instant claims 22 and 26).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1,5, 7, 10-22 and 26 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 5, 7, 8, 11, 12, 15, 16, 18 and 20-29 of copending Application No. 17/921,794 (‘794, reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because both claim a formulation of a bispecific antibody construct comprising a buffer, a saccharide, a surfactant and a pH of about 4.8-5.3 or of 4-6 (claim 1 of each). Both constructs bind CD3 and comprise a variable heaving and light chain (VH and VL, respectively), e.g. from a Fab or scFv (claims 21 and 22(#2) of ‘794 and instant claims 14-15) and hinge-CH2-CH3 regions (claim 1 of ’452 and instant claim 22(#1)). The formulations of both comprise a buffer, e.g., glutamate, a surfactant, e.g., polysorbate 80, and sucrose (claims 7, 8, 11,12, 15, 16 and 20 of ‘794 and instant claims 5, 7 and 10), including wherein the antibody construct concentration is from 10-20 mg/ml (claims 1 and 18 of ‘794, and instant claim 11). Because instant claim 1 recites the pH as “from about 4.8 to about 5.5”, this encompasses the pHs of ‘794 because the instant specification defines “about” as meaning “the recited number plus or minus 5%, 10%, 15% or more of that recited number.” ([0048]) The specification in [0047] says, “For example, "a pH from about pH 4.8 to about pH 5.5," could be, but is not limited to, pH 4.6, 5.2, 5.5 etc….” Therefore, the pH ranges of the formulation for each application overlap. The bispecific antibody construct sequences in instant claims 17-21 are the same as the respective sequences in claims 29 and 25-28 of ’794, i.e., the SEQ ID NOs are the same between applications, and both claim wherein the target antigen is DLL3 (instant claim 16 and claim 24 of ‘794). The concentration of low molecule weight (LMW) clipping product and high molecule weight (HMW) aggregates are inherent to the formulation and storage conditions (instant claims 22 and 26).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1, 2, 5, 7, 10-22 and 26 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-6, 8-12, 18, 21, 22, 24 and 26 of copending Application No. 18/022,685 (‘685, reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because both claim a liquid (aqueous) formulation of a bispecific antibody construct (claim 1 of each), comprising a buffer, e.g., glutamate, a saccharide, e.g., sucrose, a surfactant, e.g., polysorbate 80, and having a pH from about 4.8 to 5.5 (instant claim 1, 5, 7, 10) or about 4 to about 7, including 4.2 (claims 1-6 and 8-11 of ‘685), which pHs overlap in view of the definition in the instant specification of “about” as meaning “the recited number plus or minus 5%, 10%, 15% or more of that recited number.” ([0048]) Both claim wherein a binding domain is binds CD3 and construct is a single chain construct which also comprises a third domain of hinge-CH2-CH3-linker-hinge-CH2-CH3 (claims 21, 22, 24 of ‘685, and instant claims 12-15). The antibody construct is in a concentration of 1-20 mg/ml (claim 12 of ‘685 and instant claim 11). The bispecific antibody construct sequences in instant claim 21 and claim 26 of ‘685 are the same and comprise the VH and VL and CDRs thereof of CD3- and DLL3-binding scFvs (SEQ ID NO:76). The concentration of low molecule weight (LMW) clipping product and high molecule weight (HMW) aggregates are inherent to the formulation and storage conditions (instant claims 22 and 26). Note that the instant formulation “comprises” the listed ingredients and so may have more than those, e.g.¸ may have methionine. A two-way analysis of obviousness-type double patenting is not necessary.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1, 2, 5, 7 and 10-12 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 30-41, 45, 50 and 51, 43, 46, 62 and 64-68 of copending Application No. 19/022,064 (‘064, reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because both claim a composition or formulation of a bispecific antibody construct comprising an antigen-binding protein, comprising a buffer, e.g., glutamate, a saccharide, e.g., sucrose or sorbitol, a surfactant, e.g., polysorbate 80, and having a pH from about 4.8 to 5.5 (instant claim 1, 5, 7, 10) or about 3.5 to about 5, including 4.2 (claims 1, 2, 30-41, 45 and 50 of ‘064), which pHs overlap in view of the definition in the instant specification of “about” as meaning “the recited number plus or minus 5%, 10%, 15% or more of that recited number.” ([0048]). The definition of a “heterodimeric antibody” in [0065] of ‘064, the heterodimeric antibody that binds CD3 of claim 3 of ‘064 encompasses or at least makes obvious a bispecific antibody of instant claim 12. The antibody construct is in a concentration of 0.1-8 mg/ml (claim 60 of ‘064 and instant claim 11).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1, 2, 5, 7, 10-15, 22 and 26 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2, 6, 22, 24, 25, 27 and 28 of copending Application No. 19/024,641 (‘641, reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because both claim a liquid (aqueous) formulation of a bispecific antibody construct (claim 1 of each), comprising a buffer, e.g., glutamate, a saccharide, e.g., sucrose, a surfactant, e.g., polysorbate 80, and having a pH from about 4.8 to 5.5 (instant claim 1) or 4.0 to 5.0 (claims 1 and 22 of ‘641), including 4.2 (claims 27 of ‘641), which pHs overlap in view of the definition in the instant specification of “about” as meaning “the recited number plus or minus 5%, 10%, 15% or more of that recited number.” (instant [0048]). They claim wherein one binding domain binds CD3 and the other binds DLL3 (claim 1 and 6 of ‘641, and instant claims 12 and 16). The construct may be or comprise a single chain antibody construct (claim 2 of ‘641 and instant claims 14-15). The antibody construct is in a concentration of 0.1-8 mg/ml (claim 28 of ‘641 and instant claim 11). The polyol of claim 24 of ‘641 includes sucrose and sorbitol (instant claim 5, see definition in [0279] of ‘641). The concentration of low molecule weight (LMW) clipping product and high molecule weight (HMW) aggregates are inherent to the formulation and storage conditions (instant claims 22 and 26).
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1-3, 5, 7, 10-12, 14-17, 19, 22 and 26 rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-17 of U.S. Patent No. 11,918,650 B2 (‘650). Although the claims at issue are not identical, they are not patentably distinct from each other because claim 1 of ‘650 recites a pharmaceutical composition comprising a first CD3-binding domain and a second binding domain in a concentration of 0.5 μg/ml to 20 mg/ml in a buffer, e.g.¸ acetate or succinate, and wherein the concentration of high molecular weight (HMW) species is below 5%. Claims 13 and 15 specifies the composition is liquid and comprises no more than 5% multimers. Claim 2 of ‘650 adds the pH is 4.0-7.5, wherein the bispecific antibody comprises two monomers, each comprising a hinge, CH2 and CH3 domain, in a single chain format. Claim 9 of ‘650 adds an excipient or combination thereof, e.g., sucrose and polysorbate 80. This encompasses instant claims 1-3, 5, 7, 10-15. The second binding domain of claims 11-12 of ‘650 of the bispecific antibody binds DLL3, wherein the CDRs of SEQ ID NO:94-96 and 97-99 are within a VH and VL, respectively, are comprised by instant SEQ ID NO:73 and 74, respectively, and identical to instant SEQ ID NO:67-72. The concentration of low molecule weight (LMW) clipping product and high molecule weight (HMW) aggregates are inherent to the formulation and storage conditions (instant claims 22 and 26) and obvious over claims 1 and 15 of ‘650.
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim(s) 1-3, 5, 7 and 10-21 is/are rejected under 35 U.S.C. 102(a)(2) as being anticipated by US Patent 11,918,650 B2 (‘650).
The applied reference has a common Applicant and inventor with the instant application. Based upon the earlier effectively filed date of the reference, it constitutes prior art under 35 U.S.C. 102(a)(2). This rejection under 35 U.S.C. 102(a)(2) might be overcome by: (1) a showing under 37 CFR 1.130(a) that the subject matter disclosed in the reference was obtained directly or indirectly from the inventor or a joint inventor of this application and is thus not prior art in accordance with 35 U.S.C. 102(b)(2)(A); (2) a showing under 37 CFR 1.130(b) of a prior public disclosure under 35 U.S.C. 102(b)(2)(B) if the same invention is not being claimed; or (3) a statement pursuant to 35 U.S.C. 102(b)(2)(C) establishing that, not later than the effective filing date of the claimed invention, the subject matter disclosed in the reference and the claimed invention were either owned by the same person or subject to an obligation of assignment to the same person or subject to a joint research agreement.
‘650 teaches a pharmaceutical composition comprising a bispecific antibody construct comprising a first CD3-binding domain and a second binding domain in a concentration of 0.5 μg/ml to 20 mg/ml a buffer, e.g.¸ acetate or succinate, at a pH between 4-7.5, wherein the construct may be a single chain antibody construct, including in the form of hinge-CH2-CH3-linker-hinge-CH2-CH3 (col. 4, lines 4-11, 23-40, 57-67). It is also taught wherein the pharmaceutical composition further comprises one or more excipients, e.g., sucrose and polysorbate 80, or combination thereof (col. 5, lines 8-17). Table 4 teaches a bispecific antibody construct composition wherein the buffer is a glutamate buffer and wherein the composition also includes polysorbate 80 and sucrose, and the construct concentration is 0.8 mg/mL. The composition may be liquid (col. 6, lines 41-43). The second binding domain binds DLL3, comprising CDRs of SEQ ID NO:94-96 and 97-99 within a VH and VL, respectively (col. 5, lines 27-31 and col. 6, lines 1-5). SEQ ID NO:103 of ‘650 is identical to instant SEQ ID NO:76 and comprises the DLL3 VH and VL sequence of instant SEQ ID NO:73 and 74 and CDRs thereof of instant SEQ ID NO:67-72, and first CD3-binding domain VH and VL of SEQ ID NO:7 and 8 and CDRs thereof of instant SEQ ID NO:1-6.
Claim(s) 1-3, 5, 7 and 10-21 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by WO 2018/204907 A1 (Abel, cited in the IDS filed 9/29/2023).
Abel teaches a pharmaceutical composition comprising a bispecific antibody construct comprising a first CD3-binding domain and a second binding domain in a concentration of 0.5 μg/ml to 20 mg/ml a buffer, e.g.¸ acetate or succinate, at a pH between 4-7.5, wherein the construct may be a single chain antibody construct, including in the form of hinge-CH2-CH3-linker-hinge-CH2-CH3 ([12]-[16] and [19]-[20]). It is also taught wherein the pharmaceutical composition further comprises one or more excipients, e.g., sucrose and polysorbate 80, or combination thereof ([24]). Table 4 teaches a bispecific antibody construct composition wherein the buffer is a glutamate buffer and wherein the composition also includes polysorbate 80 and sucrose, and the construct concentration is 0.8 mg/mL. The composition may be liquid ([30]). The second binding domain binds DLL3, comprising CDRs of SEQ ID NO:94-96 and 97-99 within a VH and VL, respectively ([27]-[28]). SEQ ID NO:103 of Able is identical to instant SEQ ID NO:76 and comprises the DLL3 VH and VL sequence of instant SEQ ID NO:73 and 74 and CDRs thereof of instant SEQ ID NO:67-72, and first CD3-binding domain VH and VL of SEQ ID NO:7 and 8 and CDRs thereof of instant SEQ ID NO:1-6.
Claim(s) 1-3, 5, 7 and 10-21 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by WO 2017/021349 A1 (Raum).
Raum teaches a bispecific antibody construct that binds CD3 and DLL3 in an aqueous formulation that comprises a buffer, e.g., acetate for a pH of about 4-5.5, and may comprise also a surfactant, such as Tween® 80 (polysorbate), a stability enhancing agent, such as sucrose or sorbitol (p. 73, last paragraph, and p. 75, first and second paragraphs). The composition may be liquid (e.g., p. 76, second paragraph). The bispecific antibody construct comprises a first binding domain that binds DLL3 and a second binding domain that binds CD3. The anti-DLL3/CD3 scFv bispecific antibody has the sequence of SEQ ID NO:438, which is identical to instant SEQ ID NO:76 and comprises the DLL3 VH and VL sequence of instant SEQ ID NO:73 and 74 and CDRs thereof of instant SEQ ID NO:67-72, and first CD3-binding domain VH and VL of instant SEQ ID NO:7 and 8 and CDRs thereof of instant SEQ ID NO:1-6. The bispecific antibody can have the in addition to the two antigen-binding domains, a third domain having the structure of hinge-CH2-CH3-linker-hinge-CH2-CH3 (p. 41, third paragraph).
Examiner’s Comment
Because of the conflicting data present for % LMW in Tables 1-4 and corresponding figures, claim 22 is being rejected under both 35 USC 112(a) and nonstatutory double patenting. This is because of the conflicting data for % LMW, which causes the limitations of claim 22 to have not been sufficiently described in the specification and, therefore, not meet the written description proviso under 35 USC 112(a), but also to potentially be an inherent property of some of the embodiments of the invention so that it is rejected under double patenting.
Conclusion
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Claire Kaufman
/Claire Kaufman/
Primary Examiner, Art Unit 1674
February 6, 2026
/VANESSA L. FORD/Supervisory Patent Examiner, Art Unit 1674