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 .
DETAILED ACTION
Election/Restrictions
Applicant’s election without traverse of species: antibody concentration of 1 mg/ml +/- 0.1 mg/ml to 200 mg/ml +/- 20 mg/ml, sodium acetate concentration 10 mM +/- 1mM to 50 mM +/- 5 mM, polysorbate concentration of 0.01% +/- 0.005% to 0.5% +/- 0.05%, sucrose concentration 5% +/- 1% to 20% to +/- 4% w/v, pH of 5.0 +/- 0.5, SEQ ID NO: 16, vial as the species of container, intravenous administration, and 0.1 mg to 500 mg as the unit dosage antibody in the reply filed 10/05/2023 is acknowledged.
Claim 65 is withdrawn from consideration pursuant to 37 CFR1.142(b) as being drawn to nonelected inventions and species, there being no allowable generic or linking claims. Election was made in the reply filed 10/05/2023.
Claims 1, 3-4, 10-12, 15-16, 18, 20, 49-50, 53-58, 60, 62-64, 66-70, 76-77, 82, and 88 are now under consideration in the instant Office Action.
Modified Rejections Necessitated by Amendment
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 1, 3-4, 10-12, 15-16, 18, 20, 49-50, 53-58, 60, 62-64, 66-70, 76-77, 82, and 88 are rejected under 35 U.S.C. 103 as being unpatentable over Haber et al. (US 10738130 B2, in PTO-892 filed 01/03/2024) in view of Dix et al. (US 20190367624 A1, in PTO-892 filed 01/03/2024), and Wei et al. (in instant PTO-892).
Haber et al. teaches bispecific antigen-binding molecules that bind to both MUC16 and CD3. Haber et al. teaches the following sequences, which are 100% matches to sequences taught in the instant application.
Instant SEQ ID NO: 4, which encompasses SEQ ID NOs: 7-9 as CDRs, is a 100% match to Haber’s SEQ ID NO: 18.
Instant SEQ ID NO: 5, which encompasses SEQ ID NOs: 10-12 as CDRs, is a 100% match to Haber’s SEQ ID NO: 1961 and SEQ ID NO: 2.
Instant SEQ ID NO: 6, which encompasses SEQ ID NOs: 13-15 as CDRs, is a 100% match to Haber’s SEQ ID NO: 26.
Instant SEQ ID NO: 16, which is the light chain encompassing SEQ ID NOs: 13-15 as CDRs and SEQ ID NO: 6 as the light chain variable region, is a 100% match to Haber’s SEQ ID NO: 1959 and SEQ ID NO: 1.
Instant SEQ ID NO: 3, which is the heavy chain constant region, is a 100% match to Haber’s SEQ ID NO: 1960.
This meets the limitations of instant claims 1, 49, 50, 53-58, 60, 63-64, and 66-67 wherein the SEQ ID NOs: 3, 4, 5, 6, and 16 are recited as the heavy and light chain variable regions, heavy chain constant region, and light chain regions. Haber et al. also teaches “bispecific antigen-binding molecules of the present invention will typically comprise two multimerizing domains, e.g., two Fc domains that are each individually part of a separate antibody heavy chain. The first and second multimerizing domains may be of the same IgG isotype such as, e.g., IgG1/IgG1, IgG2/IgG2, IgG4/IgG4. Alternatively, the first and second multimerizing domains may be of different IgG isotypes such as, e.g., IgG1/IgG2, IgG1/IgG4, IgG2/IgG4, etc.”, see pg. 36, column 38. This meets the limitations of instant claims 57, 58, and 62 wherein the bispecific antibody is a human IgG or isotype IgG4.
However, Haber is silent on a formulation for the instantly claimed antibody. Dix et al. remedies this deficiency.
Dix et al. teaches an antibody pharmaceutical formulation which exhibits a substantial degree of antibody stability after storage for several months. Dix et al. teaches a pharmaceutical formulation “wherein the antibody is at a concentration of 150 mg/mL ±50 mg/ml”, see claim 3. This meets the limitations of instant claims 1, 3, 4, 17, 18, 19, 20, 54, 55, 56, and 76 wherein the antibody concentration falls within the claimed ranges. Dix et al. teaches the “buffer comprises acetate at a concentration of 12.5 mM±1.85 mM”, see reference’s claim 7. This meets the limitations of instant claims 1, 17, 18, 19, 20, 54, 55, 56, and 76 wherein the buffer is an acetate buffer at the claimed concentration. Instant claim 7 recites an acetate buffer than ranges from 30 mM ± 3 mM. While Dix does not explicitly teach that concentration, it would be routine to optimize the buffer concentration. Dix et al. teaches an “organic cosolvent is polysorbate 20 at a concentration of 0.2% ± 0.03% w/v”, see claim 11 of the reference. This meets the limitations of instant claims 1, 10, 11, 12, 17, 18, 19, 20, 54, 55, 56, and 76 wherein the organic co-solvent is polysorbate 20 in the claimed range. Dix et al. teaches a concentration of “about 9.0% ±1.35%; or about 10.0% ±1.5% sugar (e.g., sucrose)”, see paragraph 0076 of the reference. This meets the limitations of instant claims 1, 15, 16, 17, 18, 19, 20, 54, 55, 56, 76 wherein the sucrose concentration is within the claimed ranges. Dix et al. also teaches a “pH 5.0, acetate [buffer]”, see Table 4. This meets the limitations of instant claims 1, 17, 18, 19, 20, and 76 wherein the pH is 5.0 ± 0.5.
Dix et al. teaches that the liquid pharmaceutical formulation of any of the preceding aspects is provided in a container. In one embodiment, the container is a glass vial”, see paragraph 0047. This meets the limitations of instant claims 69, 70, and 88 wherein the pharmaceutical formulation is contained within a glass vial. Dix et al. teaches that the “pharmaceutical formulations can be administered to a patient by parenteral routes such as injection (e.g., subcutaneous, intravenous, intramuscular, intraperitoneal, etc.) or percutaneous, mucosal, nasal, pulmonary or oral administration”, see paragraph 0100. This meets the limitations of instant claims 77 wherein the formulation is administered intravenously. Dix et al. teaches how “microinfusors are particularly useful for the delivery of large doses of therapeutic proteins contained within high concentration (e.g., about 100, 125, 150, 175, 200 or more mg/mL) or viscous solutions”, see paragraph 0101. This meets the limitations of instant claim 82 wherein the unit dosage is within the range taught by Dix et al.
Haber et al. and Dix et al. do not teach about glycated species following antibody storage. Wei et al. remedies this deficiency.
On page 587, Wei et al. teaches that during the storage of therapeutic mAbs, glycation can be introduced by reducing sugars in the formulation such as sucrose. The presence of reducing sugars in the formulation has produced protein glycation even in the solid state after lyophilization. The acidic pH and elevated temperature can cause accelerated sucrose hydrolysis, leading to the production of reducing sugars and subsequent glycation. The speed of the Maillard reaction also depends on formulation buffer salt components and the type of sugar in the formulation buffers. Nevertheless, the overall glycation rate in optimized storage conditions is minimal to none. Several studies have shown that formulation, storage temperature, and storage duration affect the rate of glycation. Stability data from studies using formulation stored at 4–5 °C for up to 21/months showed a minimal or low to no increase in the level of glycation. The same formulations stored at elevated temperatures from 29 to 37 °C for 1–21/months showed significant increases in glycation levels. Based on these observations, the use of accelerated stability data are of questionable value for predicting protein stability in sucrose-containing formulations stored at 2–8 °C, where little or no glycation was observed. The results of studies on antibody glycation during storage are summarized in Table 1.
Instant claims 1, 49, 54-56, and 68 are drawn to descriptions of glycated species of the antibody after storage at various temperatures ranging from 6 to 24 months. With respect to the limitations regarding changes in percentages of glycated species after storage as compared to other formulations, this is a property of the composition itself when stored in formulation. Chemical compounds and their properties are inseparable (In re Papesch, 315 F.2d 381, 137 USPQ 43 (CCPA1963)), as are their processes and yields (In re Von Schickh, 362 F.2d 821, 150 USPQ 300 (CCPA 1966)). Thus, absent evidence to the contrary, these properties are inherent to such compositions in Haber et al. and Dix et al. as those compositions meet all of the structural elements of the claims. It would be obvious that the antibody of Haber et al., which is identical to the instantly claimed antibody, in the solution taught by Dix et al. would exhibit the same characteristics when stored under the same conditions. Wei et al. teaches the nature of monoclonal antibodies in formulation when stored at various temperatures, including the glycation of proteins when in similar conditions to the claimed invention.
It would be expected, absent evidence to the contrary, that providing the antibody of Haber et al. in the formulation of Dix et al. would provide stability for storage. Additionally, KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007), discloses that if a technique has been used to improve one method, and a person of ordinary skill would recognize that it would be used in similar methods in the same way, using the technique is obvious unless its application is beyond that person’s skill. It would be obvious to apply a known technique to a known product to be used in a known method that is ready for improvement to yield predictable results. Thus, the combination of prior art references as combined provided a prima facie case of obviousness, absent convincing evidence to the contrary. MPEP 2144.05 states that “generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. “[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, 456, 105 USPQ 233, 235 (CCPA 1955). The determination of pH and specific combinations of common components in the instant composition, including the buffer, surfactant, and stabilizer concentrations, requires only routine experimentation for one of ordinary skill in the art. Therefore, given that combination of the claimed components has been previously described, without specific evidence that the indicated concentrations and pH are critical to the formulation, the identification of these properties will not render the subject matter patentable.
Additionally, dependent claims 3-4, 10-12, 15-16, 18, 20, 54-56, and 82 recite various ranges that fall within the wider claimed ranges in instant claim 1. However, that fact does not avoid a finding of prima facie obviousness in light of the overlap of the claimed ranges. “Selecting a narrow range from within a somewhat broader range disclosed in a prior art reference is no less obvious than identifying a range that simply overlaps a disclosed range.” In re Peterson, 315 F.3d at 1329—30.
Because a skilled person in the art would attempt to identify the optimal formulation for antibody storage and dosing schedule when used as a therapeutic and would increase the dose accordingly to reach the optimum dosing strategy, the instant invention is obvious over the teachings of Haber et al. and Dix et al. “(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, 220F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955).
See MPEP 2144.05.III.A, which states that applicants can rebut a prima facie case of obviousness by showing the criticality of the range. "The law is replete with cases in which the difference between the claimed invention and the prior art is some range or other variable within the claims. . . . In such a situation, the applicant must show that the particular range is critical, generally by showing that the claimed range achieves unexpected results relative to the prior art range." In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). Thus, the burden is on the applicant to demonstrate that a particular, more narrowly claimed range shows unexpected results. Types of unexpected results include greater than expected results, superiority of a property shared with the prior art, presence of an unexpected property, or absence of an expected property (see MPEP 716.02(a)I. There is no evidence that the assortment of narrower ranges that are in the instant claims shows unexpected results compared to the teachings of the prior art.
It would be obvious at the time of the instant invention to use the bispecific antibody taught by Haber et al., with the antibody formulation taught by Dix et al. which “exhibits a substantial degree of antibody stability after storage for several months”, see Introduction, with the teachings of Wei et al. which teach antibody glycation behavior after storage in formulation for up to 24 months resulting in certain amounts of glycated species. One would be motivated to combine the bispecific antibody with the antibody formulation with the expectation of storing the antibody optimally prior to administration.
Therefore, claims 1, 3-4, 10-12, 15-16, 18, 20, 49-50, 53-58, 60, 62-64, 66-70, 76-77, 82, and 88 are rejected as obvious over Haber et al., Dix et al. and Wei et al.
Response to Arguments
Applicant’s arguments, see Remarks filed 07/28/2025, with respect to the teachings of Banks et al. have been fully considered and are persuasive. Therefore, the rejection was amended and all arguments regarding the teachings of Banks et al. are no longer under consideration as the reference was removed from the rejection.
Applicant's arguments filed 07/28/2025 have been fully considered but they are not persuasive.
Applicant argues that the amended claims are no longer drawn to a stable pharmaceutical formulation, but now a composition and as such, the skilled artisan would have no motivation to look into the antibody formulation art for guidance in maintaining glycated species. This is not found persuasive.
While the terminology in the preamble of the claims has changed, the prior art rejection continues to read on the claimed composition as it teaches all the necessary components of it despite what it is referred to as. Additionally, Applicant does not argue that this substantially changes the nature of the compositions or were the claims radically amended to reflect this change in identity. The references selected for the rejection teach the antibody, formulation, and motivation of making such even if the authors did not refer to their inventions as a “composition”.
Applicant argues “that HC-CDR3-Lys98 of the claimed bispecific antibody is susceptible to glycation, and that such glycation impacts antigen-binding and potency of the bispecific antibody” and “Dix doesn’t discuss glycation or mitigation strategies because glycation within a CDR residue is uncommon”. This is not found persuasive.
Haber et al. teach the claimed bispecific antibody is in its entirety, while Dix teaches the formulation it is to be stored in. Dix et al. teaches the “buffer comprises acetate at a concentration of 12.5 mM±1.85 mM”, see reference’s claim 7, and how the “pH 5.0, acetate [buffer]”, see Table 4. Applicant argues that Dix does not discuss an acetate buffer at the claimed concentration, nor does it discuss the result-effective variables behind maintaining the pH around 5.0. In regards to the concentration of buffer, it would be obvious to one of ordinary skill in the art to optimize the concentration of a buffer for a particular end result, such as a specific pH value. Dix et al. does consider this and adjust accordingly as reflected in their teachings (see rejection above), even if the authors did not explicitly refer to the “Donnan effect” that is observed during the manufacturing process. Applicant is reminded that absolute predictability is not a necessary prerequisite to a case of obviousness. Rather, a degree of predictability that one of ordinary skill would have found to be reasonable is sufficient. “Good science and useful contributions do not necessarily result in patentability.” PharmaStem Therapeutics, Inc. v. Viacell, Inc., 491 F.3d 1342 (Fed. Cir. 2007).
With respect to the limitations regarding glycation of residues within a CDR, this is a property of the composition itself when stored in formulation. Chemical compounds and their properties are inseparable (In re Papesch, 315 F.2d 381, 137 USPQ 43 (CCPA1963)), as are their processes and yields (In re Von Schickh, 362 F.2d 821, 150 USPQ 300 (CCPA 1966)). Thus, absent evidence to the contrary, these properties are inherent to such compositions in Haber et al. and Dix et al. as those compositions meet all of the structural elements of the claims. It would be obvious that the antibody of Haber et al., which is identical to the instantly claimed antibody, in the solution taught by Dix et al. would exhibit the same characteristics when stored under the same conditions.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SELAM BERHANE whose telephone number is (571)272-6138. The examiner can normally be reached Monday - Friday, 9-5.
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/SELAM BERHANE/Examiner, Art Unit 1675
/AURORA M FONTAINHAS/Primary Examiner, Art Unit 1675