Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claims 1-6, 8-14, 18, 20-22, 24, 26-28, 32 and 55 are pending.
Applicant’s election of Group I that read on (A) sucrose as the polysaccharide, (B) polysorbate 80 as the surfactant, (C) glutamate as the buffer, and (D) SEQ ID NO: 77 as the specific bispecific antibody in the reply filed on November 6, 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)).
The request rejoinder of non-elected method (Group II and III) upon indication of allowance of the elected product is acknowledged.
Claims 28, 32 and 55 are withdrawn from further consideration by the examiner, 37 C.F.R. 1.142(b) as being drawn to non-elected inventions.
Claims 1-6, 8-14, 18, 20-22, 24, 26 and 27, drawn to a pharmaceutical formulation that read on (A) sucrose as the polysaccharide, (B) polysorbate 80 as the surfactant, (C) glutamate as the buffer, and (D) SEQ ID NO: 77 as the specific bispecific antibody, are being acted upon in this Office Action.
Priority
Applicant’ claim priority to provisional application 63/069,432, filed August 24, 2020, and 63/197,020 filed June 4, 2021, is acknowledged.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on November 13, 2025 and December 1, 2023 have been considered by the examiner and an initialed copy of the IDS is included with this Office Action.
Drawings
The drawings filed on February 22, 2023 are acceptable.
Specification
The lengthy specification has not been checked to the extent necessary to determine the presence of all possible minor errors. Applicant's cooperation is requested in correcting any errors of which applicant may become aware in the specification.
Claim rejections under - 35 U.S.C. 112
The following is a quotation 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 35 U.S.C. 112 (pre-AIA ), first paragraph:
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 1-6, 8-14, 18, 20-22, 24, 26 and 27 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
The Written Description Guidelines for examination of patent applications indicates, “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, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical characteristics and/or other 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 applicant was in possession of the claimed genus.” (see MPEP 2163).
Claim 1 encompasses a pharmaceutical formulation comprising (a) any bispecific antibody construct, (b) any saccharide, (c) any surfactant, (d) any buffer, and (e) methionine present at a molar ratio of methionine to bispecific antibody construct of about 10X to about 5000X; wherein the pH of the formulation is from about 4 to about 7.
Claim 2 encompasses the formulation of claim 1, wherein the pH of the formulation is about 4.2.
Claim 3 encompasses the formulation of claim 1, wherein the saccharide is a monosaccharide or a disaccharide.
Claim 4 encompasses the formulation of claim 1, wherein the saccharide is glucose, galactose, fructose, xylose, sucrose (elected species), lactose, maltose, trehalose, sorbitol, mannitol, or xylitol.
Claim 5 encompasses the formulation of claim 4, wherein the saccharide is sucrose.
Claim 6 encompasses the formulation of claim 1, wherein the surfactant is any nonionic surfactant.
Claim 28 encompasses the formulation of claim 6, wherein the surfactant is polysorbate 20, polysorbate 40, polysorbate 60, or polysorbate 80 (elected species).
Claim 9 encompasses the formulation of claim 6, wherein the surf actant is polysorbate 80.
Claim 10 encompasses the formulation of claim 1, wherein the buffer is an acetate buffer, a glutamate buffer (elected species), a citrate buffer, a lactic buffer, a succinate buffer, a tartrate buffer, a fumarate buffer, a maleate buffer, a histidine buffer, or a phosphate buffer.
Claim 11 encompasses the formulation of claim 10, wherein the buffer is a glutamate buffer.
Claim 12 encompasses the formulation of claim 1, wherein the formulation comprises the bispecific antibody construct at a concentration of from about 1 mg/ml to about 20 mg/ml.
Claim 13 encompasses the formulation of claim 1, wherein the formulation comprises methionine at molar ratio of methionine to bispecific antibody construct of about 50X to about 5000X.
Claim 14 encompasses the formulation of claim 1, wherein the formulation comprises about 10 mM to about 200 mM methionine.
Claim 18 encompasses the formulation of claim 1, which comprises at least about 10% less high molecule weight (HMW) species compared to a matched formulation not comprising methionine when stored for four weeks at -15'C.
Claim 20 encompasses a frozen pharmaceutical formulation comprising about 1 mg/ml to about 20 mg/mL bispecific antibody construct, sucrose, glutamic acid, polysorbate 80, and about 10 mM to about 200 mM methionine, wherein the pH of the formulation is from about 4 to about 7.
Claim 21 encompasses the formulation of claim 1, wherein the bispecific antibody construct comprises a first binding domain that binds to any target cell surface antigen and a second binding domain that binds to human CD3 on the surface of a T cell.
Claim 22 encompasses the e formulation of claim 21, further comprising a third domain comprising, in an amino to carboxyl order, hinge-CH2 domain-CH3 domain-linker- hinge-CH2 domain-CH3 domain.
Claim 24 encompasses the formulation of claim 22, wherein the bispecific antibody construct is a single chain antibody construct.
Claim 26 encompasses the formulation of claim 21, wherein the bispecific antibody construct comprises the amino acid sequence set forth in SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 33, SEQ ID NO: 43, SEQ ID NO: 44, SEQ ID NO: 45, SEQ ID NO: 55, SEQ ID NO: 65, SEQ ID NO: 66, SEQ ID NO: 76, SEQ ID NO: 77 (elected species), SEQ ID NO: 87, SEQ ID NO: 97, SEQ ID NO: 98, SEQ ID NO: 99, SEQ ID NO: 109, SEQ ID NO: 110, SEQ ID NO: 111, SEQ ID NO: 121, SEQ ID NO: 122, SEQ ID NO: 131, SEQ ID NO: 141, SEQ ID NO: 142, SEQ ID NO: 146, SEQ ID NO: 147, SEQ ID NO: 156, SEQ ID NO: 165, SEQ ID NO: 174, SEQ ID NO: 183, SEQ ID NO: 184, SEQ ID NO: 185, SEQ ID NO: 186, SEQ ID NO: 187, or SEQ ID NO: 188.
Claim 27 encompasses the formulation of claim 1, wherein the formulation comprises methionine at molar ratio of methionine to bispecific antibody construct of about 105X to about 5000X, and the bispecific antibody construct comprises the amino acid sequence set forth in SEQ ID NO: 77.
The specification discloses:
[0091] Compositions comprising 10 mM glutamate, 9% sucrose, 0.01% PS80, 50 mM methionine, pH 4.2, were prepared, each comprising one of the following bispecific antibody constructs: BiTE®-1 (PSMA×CD3), BiTE®-2 (MSLN×CD3), BiTE®-3 (CD19×CD3), BiTE®-4 (CD33×CD3), BiTE®-5 (DLL3×CD3), BiTE®-6 (FLT3×CD3), BiTE®-7 (BCMA×CD3), and BiTE®-8 (CLDN18.2×CD3). The final protein concentration for each of BiTE®-1, BiTE®-2, BiTE®-3, BiTE®-4, BiTE®-6, BiTE®-7, and BiTE®-8 in their respective compositions was 1.5 mg/ml. The final protein concentration for BiTE®-5 was 3.75 mg/ml.
[0092] Protein samples were staged at −20° C. for 24 hours to ensure complete freezing. The samples were then stored at −15° C. for four weeks. In parallel, additional samples were stored at 4° C. and 40° C. to characterize the liquid stability of the formulation with methionine. Some samples were lyophilized to assess the impact of methionine on the lyophilized cake. Lyophilized samples were stored at 4° C. and 40° C.
[0093] The time 0 and stressed samples were evaluated for HMW content by Size Exclusion Ultra High-Performance Liquid Chromatography (SE-UHPLC). SE-UHPLC separates proteins based on differences in their hydrodynamic volumes. Molecules with higher hydrodynamic volumes elute earlier than molecules with smaller volumes. The samples were loaded onto an SE-UHPLC column (BEH200, 4.6×300 mm (Waters Corporation, 186005226)), separated isocratically, and the eluent monitored by UV absorbance. Purity was determined by calculating the percentage of each separated component as compared to the total integrated area. SE-UHPLC settings were as follows: Flow rate: 0.4 mL/min; Run time: 12 min; UV detection: 280 nm; Column temperature: Ambient; Target protein load: 6 μg; Protein compatible flow cell: 5 mm.
[0094] As shown in FIG. 1, the addition of methionine reduced frozen state aggregation levels for various bispecific antibody constructs tested after one month storage at −15° C., which represents accelerated test conditions for −30° C. storage. In a representative experiment, addition of methionine reduced the appearance of HMW species by about 25% to about 85%: BiTE®-1 HMW species reduced about 30%, BiTE®-2 HMW species reduced about 27%, BiTE®-3 HMW species reduced about 36%, BiTE®-4 HMW species reduced about 75%, BiTE®-5 HMW species reduced about 80%, BiTE®-7 HMW species reduced about 76%, and BiTE®-8 HMW species reduced about 60%.
[0095] Methionine's inhibitory effect on aggregation on frozen compositions was surprising, at least in part, because methionine did not display a similar effect on liquid compositions. The impact of methionine on liquid stability was assessed after four weeks' storage at 4° C. and 40° C., and it was determined that the excipient did not impact the liquid stability of the bispecific antibody constructs tested. See FIG. 2 and FIG. 3. The percent HMW species detected in samples stored for four weeks at 4° C. was relatively unaffected by the presence of methionine in the formulation (compare the second and fourth bars in FIG. 2). Similar results were observed under accelerated storage conditions of four weeks at 40° C. (compare the second and fourth bars in FIG. 3).
[0096] In some circumstances, therapeutic protein compositions are lyophilized for storage or transport. The impact of methionine on lyophilized stability was assessed after storage for four weeks at 4° C. and 40° C. See FIGS. 4 and 5. The higher temperature represents an accelerated stability condition. It was determined that methionine did not impact the lyophilized stability of the bispecific antibody constructs tested (compare the second and fourth bars for each construct in FIGS. 4 and 5).
[0097] The addition of other amino acids and excipients to a formulation buffer comprising a BiTE molecule, 10 mM glutamate, 9% sucrose, 0.01% PS80 did not result in a significant decrease in frozen state aggregation levels after one-month storage at −20° C. (FIGS. 6A, 6B and 6C). All proteins were evaluated at 1 mg/ml. The amino acid concentration used in FIG. 6A was 10 mM and the excipient concentration used in FIGS. 6B and 6C was 50 mM.
[0098] The data provided in this Example demonstrate the stability of the formulation of the disclosure comprising methionine at −10° C. to −40° C. (e.g., −20° C. to −35° C., such as −30° C.) for a variety of bispecific antibody constructs. Interestingly, methionine did not significantly inhibit aggregation in liquid formulations or impact the stability of a lyophilized formulation.
Example 2
[0099] Sample Preparation: An appropriate volume of 10 mM glutamate, 9% sucrose, 0.01% PS80, 200 mM methionine (pH 4.2) stock solution was added to 5 mg/mL BiTE®-5 (DLL3×CD3) (SEQ ID NO: 77) sample to achieve a final formulation of 10 mM glutamate, 9% sucrose, 0.01% PS80, pH 4.2 at varying methionine concentrations. The final protein concentration for BiTE®-5 was 2.5 mg/ml. All protein samples were staged at −20° C. for 24 hours to ensure complete freezing. The samples were then stored at −15° C. for 4 weeks. The t0 and stressed samples were evaluated for HMW content by SE-UHPLC.
[0100] SE-UHPLC Analysis: Stability samples were analyzed using SE-UHPLC (Size Exclusion Ultra High-Performance Liquid Chromatography) to monitor aggregation in the frozen state. Size Exclusion Ultra High-Performance Liquid Chromatography (SE-UHPLC) separates proteins based on differences in their hydrodynamic volumes. Molecules with higher hydrodynamic volumes elute earlier than molecules with smaller volumes. The samples are loaded onto an SE-UHPLC column (BEH200, 4.6×300 mm, (Waters Corporation, 186005226)), separated isocratically and the eluent is monitored by UV absorbance. Purity is determined by calculating the percentage of each separated component as compared to the total integrated area. SE-UHPLC settings are as follows: Flow rate: 0.4 mL/min, Run time: 12 min, UV detection: 280 nm, Column temperature: Ambient, Target protein load: 6 μg, Protein compatible flow cell: 5 mm.
[0101] Results: A methionine to BiTE molar ratio of 105 and higher was observed to reduce frozen state aggregation of BiTE®-5 (FIG. 7). Ratios below 105 did not protect against frozen state aggregation to the extent observed using molar ratios of at least 105.
Other than a formulation comprising a bispecific antibody comprising the amino acid sequence of SEQ ID NO: 77 (DLL3 x CD3 BiTE®-5) as set forth in claim 26, (b) a 10 mM glutamate, 9% sucrose, 0.01% polysorbate 80 (PS80), 200 mM methionine and a pH of 4.2 that reduce frozen state aggregation of BiTE-5 bispecific antibody format, the specification does not describe i. Complete structure, e.g., heavy and light chains variable domains, ii. Partial structure, e.g., six CDRs and functional features share by members of the genus of bispecific antibodies that correlated with binding to which antigen encompass by the claimed pharmaceutical formulation for treating any and all cancer.
Even assuming the bispecific antibody comprising the amino acid sequence of SEQ ID NO: 77, the specification discloses just one bispecific antibody that binds specifically to DLL3 and CD3 is not representative of genus. The specification does not describe a representative number of species falling with the scope of the genus or structural features common to the members of the genus so the one of skill in the art can visualize or recognize the member of the genus of the actual claimed bispecific antibody construct encompassed by the claimed pharmaceutical formulation.
An adequate written description must contain enough information about the actual makeup of the claimed products – “a precise definition, such as structure, formula, chemic name, physical properties of other properties, of species falling with the genus sufficient to distinguish the gene from other materials”, which may be present in “functional terminology when the art has established a correlation between structure and function” (Amgen page 1361).
At the time the invention was made, it was known in the art that antibodies have a large repertoire of distinct structures and that a huge variety of antibodies can be made to bind to a single epitope.
For example, Lloyd et al. taught that hundreds of functional antibody fragments can be isolated from an antibody library that bind to the same antigen wherein these antibodies have distinct heavy and light chain sequences (Lloyd et al. Protein Engineering, Design & Selection 2009, 22:159-168; see, e.g., Discussion).
Similarly, Edwards et al., J Mol Biol. 2003 Nov 14;334(1): 103-118, found that over 1000 antibodies, all different in amino acid sequence, were generated to a single protein; 568 different amino acid sequences identified for the V(H) CDR3 domains of these antibodies (Abstract).
Further, even minor changes in the amino acid sequence of a heavy or light variable region, particularly the CDRs, may dramatically affect antigen-binding function and IgG binding to the neonatal Fc receptor (FcRn) and pharmacokinetics.
For example, Piche-Nicholas et al MABS 10(1): 81-94, 2018; PTO 892) teaches altering complementary-determining region (CDRs) by 1-5 mutations significantly alter binding affinity to FcRn in vitro, see entire document, abstract, p. 95, right col, in particular. Engineering CDRs by modify local charge and thus maintain affinity to FcRn at 400 nM or weaker in vitro while retaining antigen binding may have far-reaching implications in the half-life optimization efforts of IgG therapeutics with respect to in vivo pharmacokinetics, see p. 90, in particular. Given that hundreds of unique antibody structures may bind a single antigen, the structure of an antibody cannot be predicted from the structure of the antigen (as held in Amgen), and a single species, or small group of species, cannot define a structure-function relationship so as to be representative of all the antibodies that bind to that antigen (as held in Abbvie).
Further, given the lack of guidance as to the binding specificity of the bispecific antibody in the formulation, it is unpredictable which cancer can be treated with the claimed formulation. Thus a skilled artisan would reasonably conclude that applicant was not in possession of the full breadth of the claims at the time the instant application was filed.
Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111, makes clear 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.).
Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method for isolating it. See Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016.
One cannot describe what one has not conceived. See Fiddles v. Baird, 30 USPQ2d 1481, 1483. In Fiddles v. Baird, claims directed to mammalian FGF’s were found unpatentable due to lack of written description for the broad class. The specification provided only the bovine sequence. Thus, the specification fails to describe these DNA sequences.
For genus claims, an adequate written description of a claimed genus requires more than a generic statement of an invention's boundaries. A patent must set forth either a representative number of species falling within the scope of the genus or structural features common to the members of the genus. Kubin, Exparte, 83 USPQ2d 1410 (Bd. Pat. App. & Int. 2007); Ariad Pharms., Inc. v. Eli Lilly& Co., 598 F.3d 1336, 1350 (Fed. Cir. 2010).
Therefore, only a formulation comprising (a) a bispecific antibody comprising the amino acid sequence of SEQ ID NO: 77 (DLL3 x CD3 BiTE®-5), (b) a 10 mM glutamate, 9% sucrose, 0.01% polysorbate 80 (PS80), 200 mM methionine and a pH of 4.2 for treating DLL3 expressing cancer, 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).
Claims 1-6, 8-14, 18, 20-22, 24, 26 and 27 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a formulation comprising (a) a bispecific antibody comprising the amino acid sequence of SEQ ID NO: 77 (DLL3 x CD3 BiTE®-5), (b) a 10 mM glutamate, 9% sucrose, 0.01% polysorbate 80 (PS80), 200 mM methionine and a pH of 4.2 for treating DLL3 expressing cancer, does not reasonably provide enablement for a pharmaceutical formulation as set forth in claims 1-6, 8-14, 18, 20-22, 24, 26 and 27 for treating any cancer. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
Factors to be considered in determining whether undue experimentation is required to practice the claimed invention are summarized In re Wands (858 F2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988)). The factors most relevant to this rejection include the nature of the invention, the state of the prior art, the relative skill of those in the art, the amount of direction or guidance disclosed in the specification, the presence or absence of working examples, the predictability or unpredictability of the art, the breadth of the claims, and the quantity of experimentation which would be required in order to practice the invention as claimed.
Enablement is not commensurate in scope with claims as how to make and use the bispecific antibody construct.
Claim 1 encompasses a pharmaceutical formulation comprising (a) any bispecific antibody construct, (b) any saccharide, (c) any surfactant, (d) any buffer, and (e) methionine present at a molar ratio of methionine to bispecific antibody construct of about 10X to about 5000X; wherein the pH of the formulation is from about 4 to about 7.
Claim 2 encompasses the formulation of claim 1, wherein the pH of the formulation is about 4.2.
Claim 3 encompasses the formulation of claim 1, wherein the saccharide is a monosaccharide or a disaccharide.
Claim 4 encompasses the formulation of claim 1, wherein the saccharide is glucose, galactose, fructose, xylose, sucrose (elected species), lactose, maltose, trehalose, sorbitol, mannitol, or xylitol.
Claim 5 encompasses the formulation of claim 4, wherein the saccharide is sucrose.
Claim 6 encompasses the formulation of claim 1, wherein the surfactant is any nonionic surfactant.
Claim 28 encompasses the formulation of claim 6, wherein the surfactant is polysorbate 20, polysorbate 40, polysorbate 60, or polysorbate 80 (elected species).
Claim 9 encompasses the formulation of claim 6, wherein the surf actant is polysorbate 80.
Claim 10 encompasses the formulation of claim 1, wherein the buffer is an acetate buffer, a glutamate buffer (elected species), a citrate buffer, a lactic buffer, a succinate buffer, a tartrate buffer, a fumarate buffer, a maleate buffer, a histidine buffer, or a phosphate buffer.
Claim 11 encompasses the formulation of claim 10, wherein the buffer is a glutamate buffer.
Claim 12 encompasses the formulation of claim 1, wherein the formulation comprises the bispecific antibody construct at a concentration of from about 1 mg/ml to about 20 mg/ml.
Claim 13 encompasses the formulation of claim 1, wherein the formulation comprises methionine at molar ratio of methionine to bispecific antibody construct of about 50X to about 5000X.
Claim 14 encompasses the formulation of claim 1, wherein the formulation comprises about 10 mM to about 200 mM methionine.
Claim 18 encompasses the formulation of claim 1, which comprises at least about 10% less high molecule weight (HMW) species compared to a matched formulation not comprising methionine when stored for four weeks at -15'C.
Claim 20 encompasses a frozen pharmaceutical formulation comprising about 1 mg/ml to about 20 mg/mL bispecific antibody construct, sucrose, glutamic acid, polysorbate 80, and about 10 mM to about 200 mM methionine, wherein the pH of the formulation is from about 4 to about 7.
Claim 21 encompasses the formulation of claim 1, wherein the bispecific antibody construct comprises a first binding domain that binds to any target cell surface antigen and a second binding domain that binds to human CD3 on the surface of a T cell.
Claim 22 encompasses the e formulation of claim 21, further comprising a third domain comprising, in an amino to carboxyl order, hinge-CH2 domain-CH3 domain-linker- hinge-CH2 domain-CH3 domain.
Claim 24 encompasses the formulation of claim 22, wherein the bispecific antibody construct is a single chain antibody construct.
Claim 26 encompasses the formulation of claim 21, wherein the bispecific antibody construct comprises the amino acid sequence set forth in SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 33, SEQ ID NO: 43, SEQ ID NO: 44, SEQ ID NO: 45, SEQ ID NO: 55, SEQ ID NO: 65, SEQ ID NO: 66, SEQ ID NO: 76, SEQ ID NO: 77 (elected species), SEQ ID NO: 87, SEQ ID NO: 97, SEQ ID NO: 98, SEQ ID NO: 99, SEQ ID NO: 109, SEQ ID NO: 110, SEQ ID NO: 111, SEQ ID NO: 121, SEQ ID NO: 122, SEQ ID NO: 131, SEQ ID NO: 141, SEQ ID NO: 142, SEQ ID NO: 146, SEQ ID NO: 147, SEQ ID NO: 156, SEQ ID NO: 165, SEQ ID NO: 174, SEQ ID NO: 183, SEQ ID NO: 184, SEQ ID NO: 185, SEQ ID NO: 186, SEQ ID NO: 187, or SEQ ID NO: 188.
Claim 27 encompasses the formulation of claim 1, wherein the formulation comprises methionine at molar ratio of methionine to bispecific antibody construct of about 105X to about 5000X, and the bispecific antibody construct comprises the amino acid sequence set forth in SEQ ID NO: 77.
The specification discloses:
[0091] Compositions comprising 10 mM glutamate, 9% sucrose, 0.01% PS80, 50 mM methionine, pH 4.2, were prepared, each comprising one of the following bispecific antibody constructs: BiTE®-1 (PSMA×CD3), BiTE®-2 (MSLN×CD3), BiTE®-3 (CD19×CD3), BiTE®-4 (CD33×CD3), BiTE®-5 (DLL3×CD3), BiTE®-6 (FLT3×CD3), BiTE®-7 (BCMA×CD3), and BiTE®-8 (CLDN18.2×CD3). The final protein concentration for each of BiTE®-1, BiTE®-2, BiTE®-3, BiTE®-4, BiTE®-6, BiTE®-7, and BiTE®-8 in their respective compositions was 1.5 mg/ml. The final protein concentration for BiTE®-5 was 3.75 mg/ml.
[0092] Protein samples were staged at −20° C. for 24 hours to ensure complete freezing. The samples were then stored at −15° C. for four weeks. In parallel, additional samples were stored at 4° C. and 40° C. to characterize the liquid stability of the formulation with methionine. Some samples were lyophilized to assess the impact of methionine on the lyophilized cake. Lyophilized samples were stored at 4° C. and 40° C.
[0093] The time 0 and stressed samples were evaluated for HMW content by Size Exclusion Ultra High-Performance Liquid Chromatography (SE-UHPLC). SE-UHPLC separates proteins based on differences in their hydrodynamic volumes. Molecules with higher hydrodynamic volumes elute earlier than molecules with smaller volumes. The samples were loaded onto an SE-UHPLC column (BEH200, 4.6×300 mm (Waters Corporation, 186005226)), separated isocratically, and the eluent monitored by UV absorbance. Purity was determined by calculating the percentage of each separated component as compared to the total integrated area. SE-UHPLC settings were as follows: Flow rate: 0.4 mL/min; Run time: 12 min; UV detection: 280 nm; Column temperature: Ambient; Target protein load: 6 μg; Protein compatible flow cell: 5 mm.
[0094] As shown in FIG. 1, the addition of methionine reduced frozen state aggregation levels for various bispecific antibody constructs tested after one month storage at −15° C., which represents accelerated test conditions for −30° C. storage. In a representative experiment, addition of methionine reduced the appearance of HMW species by about 25% to about 85%: BiTE®-1 HMW species reduced about 30%, BiTE®-2 HMW species reduced about 27%, BiTE®-3 HMW species reduced about 36%, BiTE®-4 HMW species reduced about 75%, BiTE®-5 HMW species reduced about 80%, BiTE®-7 HMW species reduced about 76%, and BiTE®-8 HMW species reduced about 60%.
[0095] Methionine's inhibitory effect on aggregation on frozen compositions was surprising, at least in part, because methionine did not display a similar effect on liquid compositions. The impact of methionine on liquid stability was assessed after four weeks' storage at 4° C. and 40° C., and it was determined that the excipient did not impact the liquid stability of the bispecific antibody constructs tested. See FIG. 2 and FIG. 3. The percent HMW species detected in samples stored for four weeks at 4° C. was relatively unaffected by the presence of methionine in the formulation (compare the second and fourth bars in FIG. 2). Similar results were observed under accelerated storage conditions of four weeks at 40° C. (compare the second and fourth bars in FIG. 3).
[0096] In some circumstances, therapeutic protein compositions are lyophilized for storage or transport. The impact of methionine on lyophilized stability was assessed after storage for four weeks at 4° C. and 40° C. See FIGS. 4 and 5. The higher temperature represents an accelerated stability condition. It was determined that methionine did not impact the lyophilized stability of the bispecific antibody constructs tested (compare the second and fourth bars for each construct in FIGS. 4 and 5).
[0097] The addition of other amino acids and excipients to a formulation buffer comprising a BiTE molecule, 10 mM glutamate, 9% sucrose, 0.01% PS80 did not result in a significant decrease in frozen state aggregation levels after one-month storage at −20° C. (FIGS. 6A, 6B and 6C). All proteins were evaluated at 1 mg/ml. The amino acid concentration used in FIG. 6A was 10 mM and the excipient concentration used in FIGS. 6B and 6C was 50 mM.
[0098] The data provided in this Example demonstrate the stability of the formulation of the disclosure comprising methionine at −10° C. to −40° C. (e.g., −20° C. to −35° C., such as −30° C.) for a variety of bispecific antibody constructs. Interestingly, methionine did not significantly inhibit aggregation in liquid formulations or impact the stability of a lyophilized formulation.
Example 2
[0099] Sample Preparation: An appropriate volume of 10 mM glutamate, 9% sucrose, 0.01% PS80, 200 mM methionine (pH 4.2) stock solution was added to 5 mg/mL BiTE®-5 (DLL3×CD3) (SEQ ID NO: 77) sample to achieve a final formulation of 10 mM glutamate, 9% sucrose, 0.01% PS80, pH 4.2 at varying methionine concentrations. The final protein concentration for BiTE®-5 was 2.5 mg/ml. All protein samples were staged at −20° C. for 24 hours to ensure complete freezing. The samples were then stored at −15° C. for 4 weeks. The t0 and stressed samples were evaluated for HMW content by SE-UHPLC.
[0100] SE-UHPLC Analysis: Stability samples were analyzed using SE-UHPLC (Size Exclusion Ultra High-Performance Liquid Chromatography) to monitor aggregation in the frozen state. Size Exclusion Ultra High-Performance Liquid Chromatography (SE-UHPLC) separates proteins based on differences in their hydrodynamic volumes. Molecules with higher hydrodynamic volumes elute earlier than molecules with smaller volumes. The samples are loaded onto an SE-UHPLC column (BEH200, 4.6×300 mm, (Waters Corporation, 186005226)), separated isocratically and the eluent is monitored by UV absorbance. Purity is determined by calculating the percentage of each separated component as compared to the total integrated area. SE-UHPLC settings are as follows: Flow rate: 0.4 mL/min, Run time: 12 min, UV detection: 280 nm, Column temperature: Ambient, Target protein load: 6 μg, Protein compatible flow cell: 5 mm.
[0101] Results: A methionine to BiTE molar ratio of 105 and higher was observed to reduce frozen state aggregation of BiTE®-5 (FIG. 7). Ratios below 105 did not protect against frozen state aggregation to the extent observed using molar ratios of at least 105.
Other than a formulation comprising a bispecific antibody comprising the amino acid sequence of SEQ ID NO: 77 (DLL3 x CD3 BiTE®-5) as set forth in claim 26, (b) a 10 mM glutamate, 9% sucrose, 0.01% polysorbate 80 (PS80), 200 mM methionine and a pH of 4.2 that reduce frozen state aggregation of BiTE-5 bispecific antibody format, the specification does not teach i. Complete structure, e.g., heavy and light chains variable domains, ii. Partial structure, e.g., six CDRs and functional features share by members of the genus of bispecific antibodies that correlated with binding to which antigen encompass by the claimed pharmaceutical formulation for treating all cancers.
Even assuming the bispecific antibody comprising the amino acid sequence of SEQ ID NO: 77, the specification discloses just one bispecific antibody that binds specifically to DLL3 and CD3 is not representative of genus.
At the time the invention was made, it was known in the art that antibodies have a large repertoire of distinct structures and that a huge variety of antibodies can be made to bind to a single epitope.
For example, Lloyd et al. taught that hundreds of functional antibody fragments can be isolated from an antibody library that bind to the same antigen wherein these antibodies have distinct heavy and light chain sequences (Lloyd et al. Protein Engineering, Design & Selection 22:159-168, 2009; see, e.g., Discussion).
Similarly, Edwards et al., J Mol Biol. 334(1): 103-118, 2003, found that over 1000 antibodies, all different in amino acid sequence, were generated to a single protein; 568 different amino acid sequences identified for the V(H) CDR3 domains of these antibodies (Abstract).
Further, even minor changes in the amino acid sequence of a heavy or light variable region, particularly the CDRs, may dramatically affect antigen-binding function and IgG binding to the neonatal Fc receptor (FcRn) and pharmacokinetics.
For example, Piche-Nicholas et al MABS 10(1): 81-94, 2018; PTO 892) teaches altering complementary-determining region (CDRs) by 1-5 mutations significantly alter binding affinity to FcRn in vitro, see entire document, abstract, p. 95, right col, in particular. Engineering CDRs by modify local charge and thus maintain affinity to FcRn at 400 nM or weaker in vitro while retaining antigen binding may have far-reaching implications in the half-life optimization efforts of IgG therapeutics with respect to in vivo pharmacokinetics, see p. 90, in particular. Given that hundreds of unique antibody structures may bind a single antigen, the structure of an antibody cannot be predicted from the structure of the antigen, and a single species, or small group of species, cannot define a structure-function relationship so as to be representative of all the antibodies that bind to that antigen.
Further, given the lack of guidance as to the binding specificity of the bispecific antibody in the formulation (claims 1-6, 8-14, 18, 20-22, 24 and 27), it is unpredictable which cancer can be treated with the claimed formulation.
Even assuming the bispecific antibody comprises the amino acid sequence of SEQ ID NO: 77 (claim 26), there are no in vivo working examples. It is not clear that the claimed formulation can treat all cancers.
For treating cancer in human, Hay et al (Nature Biotechnology 32(1): 40-51, January 2014; PTO 892) teach oncology is a particularly challenging disease area in which to achieve phase 3 success. Current animal model (e.g., xenograft tumor models in mice) can be poor predictors of clinical outcomes in humans. Additionally, recent scientific reports show that certain types of cancer, which were previously thought of as one disease, may actually comprise several subtypes of disease with different etiologies, see page 49, right col..
As such, one skilled in the art would need to resort to undue experimentation in a complex and unpredictable field in order to determine how to perform the invention in a manner commensurate in scope with the claims.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102 of this title, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negatived by the manner in which the invention was made.
The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. 103(a) are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1-6, 8-10, 12-14, 18, 21-22, 24 and 26-27 are rejected under 35 U.S.C. 103 as being unpatentable over Raum et al (WO2017021349, published February 9, 2017; PTO 892) in view of WO2019020745 publication (published Jan 31, 2019; PTO 1449) and/or WO2007109221 (published September 27, 2007; PTO 1449).
Claim 1 encompasses a pharmaceutical formulation comprising (a) a bispecific antibody construct, (b) a saccharide, (c) a surfactant, (d) a buffer, and (e) methionine present at a molar ratio of methionine to bispecific antibody construct of about 10X to about 5000X; wherein the pH of the formulation is from about 4 to about 7.
Raum teaches a formulation (p. 64, p. 72, p. 73, p. 78) comprising a DLL3xCD3 bispecific antibody construct comprising a first binding domain which binds to human DLL3 on the surface of a target cell and a second binding domain which binds to human CD3 on the surface of a T cell (see p. 20, p. 24, p. 52), surfactant (p. 72), a saccharide, e.g., sucrose (see p. 74), a surfactant, e.g., polysorbate 20 or Tween 80 (see p. 75, line 1-5), a buffer, e.g., phosphate buffer or PBS (see p. 65, p. 73, line 3) or acetate buffer (see p. 73), methionine (antioxidant, see p. 73, p. 78) and a pH of about 5.0 to 5.5, see p. 73, last line, in particular.
Regarding claim 2, the reference pH 4.0 to 5.5 includes the claimed pH of about 4.2, see p. 73, last line.
Regarding claim 3, Raum teaches that the saccharides include monosaccharide or disaccharide, preferably sucrose, see p. 74, lines 11-12.
Regarding claims 4-5, Raum teaches that the saccharides are glucose, trehalose, sucrose, sorbitol, or xylitol, see p. 74, lines 12-14.
Regarding claims 6, 8-9, Raum teaches that the surfactant is nonionic surfactant, e.g., polysorbates, such as polysorbate 20, polysorbate, triton, Tween 80 (aka polysorbate 80), see p. 75, lines 1-7, polysorbate 80, see p. 79.
Regarding claim 10, Raum teaches that examples of buffers are borate, bicarbonate, Tris-HCI, citrates, phosphates or other organic acids, succinate, phosphate, histidine, acetate, see p. 73.
Regarding claim 12, Raum teaches that the formulation comprises 2.5 mg/ml, which is within the claimed range of about 1 mg/ml to about 20 mg/ml, see para bridging p. 65 to 66.
Regarding claim 21, Raum teaches that the DLL3xCD3 bispecific antibody construct comprising a first binding domain which binds to human DLL3 on the surface of a target cell and a second binding domain which binds to human CD3 on the surface of a T cell (see p. 20, p. 24, p. 52).
Regarding claim 22, Raum teaches that the bispecific antibody further comprises a third domain comprising, in an N- to C-terminal order, a hinge-CH2-CH3-linker-hinge-CH2-CH3, p. 41, second paragraph, in particular.
Regarding claim 24, Raum teaches that the bispecific antibody is a single chain antibody construct, e.g., (scFv)2, see reference claim 4, or single chain antibody (scFv, see p. 56), in particular.
Regarding claim 26, Raum teaches that the DLL3xCD3 bispecific antibody construct comprising the amino acid sequence of SEQ ID NO: 520, which is 100% identical to the claimed SEQ ID NO: 77, see p. 201, sequence alignment below:
Query Match 100.0%; Score 5312; Length 982;
Best Local Similarity 100.0%;
Matches 982; Conservative 0; Mismatches 0; Indels 0; Gaps 0;
Qy 1 QVQLQESGPGLVKPSETLSLTCTVSGGSISSYYWSWIRQPPGKCLEWIGYVYYSGTTNYN 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 QVQLQESGPGLVKPSETLSLTCTVSGGSISSYYWSWIRQPPGKCLEWIGYVYYSGTTNYN 60
Qy 61 PSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCASIAVTGFYFDYWGQGTLVTVSSGG 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 PSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCASIAVTGFYFDYWGQGTLVTVSSGG 120
Qy 121 GGSGGGGSGGGGSEIVLTQSPGTLSLSPGERVTLSCRASQRVNNNYLAWYQQRPGQAPRL 180
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 121 GGSGGGGSGGGGSEIVLTQSPGTLSLSPGERVTLSCRASQRVNNNYLAWYQQRPGQAPRL 180
Qy 181 LIYGASSRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYDRSPLTFGCGTKLEI 240
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 181 LIYGASSRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYDRSPLTFGCGTKLEI 240
Qy 241 KSGGGGSEVQLVESGGGLVQPGGSLKLSCAASGFTFNKYAMNWVRQAPGKGLEWVARIRS 300
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 241 KSGGGGSEVQLVESGGGLVQPGGSLKLSCAASGFTFNKYAMNWVRQAPGKGLEWVARIRS 300
Qy 301 KYNNYATYYADSVKDRFTISRDDSKNTAYLQMNNLKTEDTAVYYCVRHGNFGNSYISYWA 360
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 301 KYNNYATYYADSVKDRFTISRDDSKNTAYLQMNNLKTEDTAVYYCVRHGNFGNSYISYWA 360
Qy 361 YWGQGTLVTVSSGGGGSGGGGSGGGGSQTVVTQEPSLTVSPGGTVTLTCGSSTGAVTSGN 420
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 361 YWGQGTLVTVSSGGGGSGGGGSGGGGSQTVVTQEPSLTVSPGGTVTLTCGSSTGAVTSGN 420
Qy 421 YPNWVQQKPGQAPRGLIGGTKFLAPGTPARFSGSLLGGKAALTLSGVQPEDEAEYYCVLW 480
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 421 YPNWVQQKPGQAPRGLIGGTKFLAPGTPARFSGSLLGGKAALTLSGVQPEDEAEYYCVLW 480
Qy 481 YSNRWVFGGGTKLTVLGGGGDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVT 540
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 481 YSNRWVFGGGTKLTVLGGGGDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVT 540
Qy 541 CVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPCEEQYGSTYRCVSVLTVLHQDWLNGKEYK 600
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 541 CVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPCEEQYGSTYRCVSVLTVLHQDWLNGKEYK 600
Qy 601 CKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVE 660
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 601 CKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVE 660
Qy 661 WESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKS 720
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 661 WESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKS 720
Qy 721 LSLSPGGGGSGGGGSGGGGSGGGGSGGGGSGGGGSDKTHTCPPCPAPELLGGPSVFLFPP 780
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 721 LSLSPGGGGSGGGGSGGGGSGGGGSGGGGSGGGGSDKTHTCPPCPAPELLGGPSVFLFPP 780
Qy 781 KPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPCEEQYGSTYRCVSV 840
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 781 KPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPCEEQYGSTYRCVSV 840
Qy 841 LTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSL 900
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 841 LTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSL 900
Qy 901 TCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSC 960
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 901 TCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSC 960
Qy 961 SVMHEALHNHYTQKSLSLSPGK 982
||||||||||||||||||||||
Db 961 SVMHEALHNHYTQKSLSLSPGK 982
Raum does not teach the molar ratio of methionine to antibody construct is about 10x to about 5000x as per claim 1 or about 50x to about 5000x as per claim 13 or wherein the formulation comprises about 10 mM to about 200 mM methionine as per claim 14.
However, the WO2019020745 publication teaches pharmaceutical formulation comprising 1 to 200 mg/ml of a bispecific antibody which binds to carcinoembryonic antigen (CEA) and CD3 (CEA CD3 bispecific antibody, p. 5, lines 23-27), 1 to 100 mM of a buffering, 0.001 to 1% of a surfactant, 1 to 500 mM of at least one stabilizer, and a pH in the range from 4.0 to 7.0, see entire document, abstract, p. 1, in particular.
Preferred pharmaceutically acceptable buffers comprise but are not limited to histidine buffers, citrate buffers, succinate buffers, acetate buffers and phosphate buffers as per claim 10, see p. 1-2.
Examples of non-ionic surfactant include polysorbate 20 (polyoxyethylene sorbitan monolaureate, sold under the trademark Tween 20™) and polysorbate 80 (polyoxyethylene sorbitan monooleate, sold under the trademark Tween 80™) as per claims 6, 8-9, see p. 2.
Saccharides for use in the present invention are sucrose as per claim 4, see p. 3, line 28. Saccharides can be present in the formulation in an amount of about 100 to about 500 mM, preferably in an amount of about 200 to about 300 mM, more preferably in an amount of about 220 to about 250 mM, particularly an amount of about 230 mM or about 240 mM, most preferably in an amount of about 230 mM.
Antioxidants, e.g., methionine can be used in an amount of about 0.01 to about 100 mM, preferably in an amount of about 5 to about 50 mM and more preferably in an amount of about 5 to about 25 mM. Methionine is preferably used at a concentration of about 5 to about 25 mM, most preferably about 10 mM, which overlaps the claimed range of about 10 mM to about 200 mM methionine as per claim 14, (see p. 4, line 10-12).
In one embodiment, the formulation comprises: 5 to 50 mg/ml of a CEA CD3 bispecific antibody, 15 to 30 mM L-histidine, 0.02 to 0.05% (w/v) polysorbate 20; 120 to 300 mM sucrose, 5 to 25 mM methionine and a pH of 5.5 + 0.5, see p. 23. The WO2019020745 publication teaches that the maximum antibody stability and antibody formulations free from particles, L-histidine/HCI buffer is the most favorable buffer, sucrose in combination with methionine are the most favorable stabilizers, and polysorbate 20 is the most favorable surfactant, see p. 32.
Likewise, the WO2007109221 publication teaches formulations exhibiting reduced aggregation by adding methionine to the formulation to a concentration of about 0.5 mM to about 145 mM, which overlaps the claimed range of about 10 mM to about 200 mM methionine as per claim 14, see entire document, Summary of invention, p. 2, in particular. The WO2007109221 publication teaches that adding methionine to a protein formulation to a concentration of about 0.5 mM to about 145 mM increases the shelf life of the protein formulation compared with a formulation lacking methionine. Examples of proteins include bispecific antibodies, see p. 2-3, p. 14-15. The WO2007109221 publication teaches that the protein of the formulation is an antibody, e.g., a bispecific antibody (see p. 20) having at least two antigen-binding site that specifically bind different antigens, see p. 21, in particular. The protein concentrations in the formulations are generally between 0.5 mg/ml and about 300 mg/ml, between about 0.5 mg/ml and about 25 mg/ml, see p. 24. The pH of a formulation is generally about pH 5.5 to about 6.5, see p. 24, in particular. The WO2007109221 publication teaches the formulation samples were stored at -800C, 25°C, and 4O0C and were evaluated for % HMW over a 4-week period by SEC-HPLC, see Example 4. Addition of methionine to formulations that were subjected to shaking resulted in a decrease in the % HMW levels to 1.0 and 2.2% compared to a matched formulation not comprising methionine when stored for four weeks (1 month), see Table 1.
In view of the combined teachings of the references, it would have been prima facie obvious to a person of ordinary skill in the art before the effective filling date of the claimed invention to combine Raum’s formation comprising a bispecific antibody comprising the amino acid sequence of SEQ ID NO: 77, a saccharide, a surfactant, a buffer, and the WO2019020745 publication’s methionine at a concentration of in an amount of about 0.01 to about 100 mM, or about 5 to about 50 mM or about 5 to about 25 mM in 5 to 50 mg/ml or the WO2007109221 publication’s methionine at a concentration of about 0.5 mM to about 145 mM to a protein formulation in order to reduce aggregation in the formulation and increases the shelf life of the formulation. Claim 14 is included as WO2019020745 publication’s about 0.01 to about 100 mM overlaps the claimed range of about 10 mM to about 200 mM. Likewise, the WO2007109221 publication’s methionine concentration of about 0.5 mM to about 145 mM overlaps the claimed range of about 10 mM to about 200 mM. Claim 18 is included as it is within the purview of ordinary skilled in the art to store the formulation at -15 °C as opposed to -80°C for four weeks prior to evaluated for % HMW over a 4-week period by SEC-HPLC as taught by the WO2007109221 publication.
One of ordinary skill in the art would have had an expectation of success at the time the invention was made to determine a molar ratio, for example, when a bispecific antibody constructed is provided at a concentration of 2.5 mg/ml, 0.125 mM methionine results in a molar ratio of 5.25. 0.25 mM methionine results in a molar ratio of 10.5 (aka about 10x), doubling of methionine to 0.50 mM results in a molar ratio of 21.0. 1.25 mM methionine results in a molar ratio of 52.5 (aka 50x). 2.5 mM of methionine results in a molar ratio of 105 (aka 105x) as per claim 27. 5.0 mM of methionine results in a molar ratio of 210. 10.0 mM of methionine results in a molar ratio of 420. 20.0 mM of methionine results in a molar ratio of 840. 25.0 mM of methionine results in a molar ratio of 1050. 50.0 mM of methionine results in a molar ratio of 2100. 100.0 mM of methionine results in a molar ratio of 4200. 120.0 mM of methionine results in a molar ratio of 5040 (aka about 5000x) as per claim 1.
Claims 13 and 27 are included because it has long been settled to be no more than routine experimentation for one of ordinary skill in the art to optimize concentration. The courts have determined that: “[W|here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 454, 105 USPQ 223,235, (CCPA 1955). Since the prior art teaches that concentrations of methionine often vary according to the bispecific antibody being analyzed, and the solutions and parameters appear to work equally as well, absent unexpected results, it would have been obvious for one of ordinary skill to discover the optimum workable concentrations of molar ratio of methionine disclosed by the prior art by normal optimization procedures known in the antibody art.
One of ordinary skill in the art would have been motivated to do so because the WO2019020745 publication teaches that methionine is one of the most favorable stabilizers, and the maximum antibody stability and antibody formulations free from particles comprise L-histidine/HCI buffer is the most favorable buffer, sucrose in combination with methionine are the most favorable stabilizers, and polysorbate 20 is the most favorable surfactant, see p. 32.
One of ordinary skill in the art would have been motivated to do so because the WO2007109221 publication teaches that adding methionine to antibody formulation increases the shelf life of the antibody formulation compared with a formulation lacking methionine. Examples of proteins include bispecific antibodies, see p. 2-3, p. 14-15. Therefore, the invention as a whole was clearly prima facie obvious to one of ordinary skill in the art at the time the invention was filed.
“The combination of familiar elements according to known method is likely to be obvious when it does no more than yield predictable results.” KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 416 (2007).
“The test of obviousness is not express suggestion of the cl aimed invention in any or all of the references but rather what the references taken collectively would suggest to those of ordinary skill in the art presumed to be familiar with them.” See In re Rosselet 146 USPQ 183, 186 (CCPA 1965).
“There is no requirement (under 35 USC 103(a)) that the prior art contain an express suggestion to combine known elements to achieve the claimed invention. Rather, the suggestion to combine may come from the prior art, as filtered through the knowledge of one skilled in the art.,” Motorola, Inc, v. Interdigital Tech. Corn., 43 USPQ2d 1481, 1489 (Fed. Cir. 1997).
Accordingly, the claimed invention as a whole was prima facie obvious to one of ordinary skill in the art before the effective filling date of the claimed invention especially in the absence of evidence to the contrary.
Claims 11 and 20 are rejected under 35 U.S.C. 103 as being unpatentable over Raum et al (WO2017021349, published February 9, 2017; PTO 892) in view of WO2019020745 publication (published Jan 31, 2019; PTO 1449) and/or WO2007/109221 publication (published September 27, 2007; PTO 1449) as applied to claims 1-6, 8-10, 12-14, 18, 21-22, 24 and 26-27 mentioned above and further in view of WO2019157340 publication (published August 15, 2019; PTO 1449).
The combine teachings of Raum, the WO2019020745 publication and/or WO2007/109221 publication have been discussed supra.
The references above do not teach the buffer in the formulation is a glutamate buffer as per claim 11 and wherein the formulation include glutamic acid as per claim 20.
However, the WO2019157340 publication teaches a formulation comprising a bispecific antibody, e.g., bispecific antibody that binds CD3 and CD38 (see para. [0065]), 10 mM glutamate buffer as per claim 11 (see para. [0070], [0026], [0088]), a saccharide, e.g., 9% (w/V) sucrose (para. [0021], [0084] to [0087]), a surfactant, e.g., 0.01% (w/V) polysorbate (see para. [0021] to [0022], [0082]), and wherein the pH of the composition is 4.2, see para. [0023], p. 6, para. [0026]. The WO2019157340 publication teaches that the typical bispecific antibody concentration ranges from about 0.1 mg/ml to about 20 mg/ml, see p. 7, line 1-3, para. [0146] to [0147]. Claim 20 is included as the WO2019157340 publication teaches that the frozen formulation (para. 0097], [0198], [0208]) can include glutamic acid as the buffering agent, see para. [0076]. The skilled person will be aware that such choice of a particular dosage form may for example influence the physical state, stability, rate of in vivo release and rate of in vivo clearance of an antibody, see para. [0199].
In view of the combined teachings of the references, it would have been prima facie obvious to a person of ordinary skill in the art before the effective filling date of the claimed invention to substituting a known buffer of Raum, the WO2019020745 publication and/or WO2007/109221 publication for another, e.g., 10 mM glutamate buffer, including glutamic acid as the buffering agent, as taught by the WO2019157340 publication to arrive at the claimed invention with a reasonable expectation of success, e.g., to minimize protein aggregation during storage, loss of function and adverse immunogenic reactions, see para. [0008].
A person of ordinary skill in the art is always motivated to pursue the known options within her or his technical grasp. If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense. KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 416 (2007).
“The test of obviousness is not express suggestion of the cl aimed invention in any or all of the references but rather what the references taken collectively would suggest to those of ordinary skill in the art presumed to be familiar with them.” See In re Rosselet 146 USPQ 183, 186 (CCPA 1965).
“There is no requirement (under 35 USC 103(a)) that the prior art contain an express suggestion to combine known elements to achieve the claimed invention. Rather, the suggestion to combine may come from the prior art, as filtered through the knowledge of one skilled in the art.,” Motorola, Inc, v. Interdigital Tech. Corn., 43 USPQ2d 1481, 1489 (Fed. Cir. 1997).
Accordingly, the claimed invention as a whole was prima facie obvious to one of ordinary skill in the art before the effective filling date of the claimed invention especially in the absence of evidence to the contrary.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to PHUONG HUYNH whose telephone number is (571)272-0846. The examiner can normally be reached on 9:00 a.m. to 6:30 p.m. The examiner can also be reached on alternate alternative Friday from 9:00 a.m. to 5:30 p.m.
If attempts to reach the examiner by telephone are unsuccessful, the examiner's supervisor, Misook Yu, can be reached at 571-270-3497. The fax phone number for the organization where this application or proceeding is assigned is 571-272-0839.
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/PHUONG HUYNH/ Primary Examiner, Art Unit 1641