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 Group I, claims 1-12 and species: 80 mg/mL to 300 mg/mL, 100 mM to 400 mM, 0.01% w/v to 0.1%, arginine hydrochloride, histidine buffer, and 10 to 100 mM as the histidine buffer concentration in the reply filed 09/26/2025 is acknowledged.
Claims 1-5, 7-12, and 22-35 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 1-5, 7-12, and 22-35 are rejected under 35 U.S.C. 103 as being unpatentable over Luthman et al. (in WO 2020/023530 A2, in IDS filed 09/19/2022), in view of Morichika et al. (US 2016/009419 A1, in PTO-892 filed 11/03/2025).
Luthman et al. teaches “methods comprising administering a composition comprising a therapeutically effective amount of at least one anti-Aβ protofibril antibody... In some embodiments, the at least one anti-Aβ protofibril antibody is BAN2401”, see Abstract. Luthman et al. teach an antibody referred to as “BAN2401”, which is a 100% sequence identity match to instant SEQ ID NOs: 1 and 2, as well as the antibody known as “lecanemab” and “Leqembi®”. Luthman et al. also teaches that the BAN2401 antibody can be supplied as any formulation suitable for administration to a human subject, for example, as a sterile, clear solution for injection containing 10 mg/mL, in a single-use 10 mL vial (total 100 mg/vial) comprising 25 mM sodium citrate, 125 mM sodium chloride, 0.02% (w/v) polysorbate 80, and having pH of 5.7 when administered intravenously, see paragraph 0689. This meets the limitations of instant claims 1 and 33 wherein the sequences to the anti-Aβ protofibril antibody are taught, instant claims 34-38 wherein the antibody taught in the reference is a match to the antibody referred to as “lecanemab” in the claims, instant claim 7 wherein the citrate buffer is 10 to 100 mM, instant claim 12 wherein the citrate buffer is 30 to 50 mM, and instant claims 1, 11, 12, 22, 33, 34, 35 wherein the pH ranges from 4.5 to 5.5.
However, Luthman et al. does not teach a high concentration antibody formulation. Morichika et al. remedies this deficiency.
Morichika et al. teaches “antibody-containing formulation, and particularly, to a stable liquid formulation containing a high concentration of an antibody”, see paragraph 0001. Morichika et al. discuss the constraints on creating a high concentration antibody formulation for administration, teaching that “designing an antibody-containing formulation for subcutaneous injection, since a dose of an antibody per administration is large (about 100 mg to 200 mg) and an amount of an injection solution is generally limited in subcutaneous injection, it is necessary to increase a concentration of an antibody in a liquid to be administered. In view of this, in many cases, high concentration formulations are used, which are prepared by the lyophilization-concentration technique, in which a lyophilized formulation is reconstituted in water having a volume smaller than that before lyophilization. However, a strong demand exists for a liquid formulation which does not require reconstitution, and which is easy to handle”, see paragraph 0003.
Morichika et al. teach a high concentration antibody dosage of “preferably has an antibody concentration of not less than 50 mg/mL, more preferably not less than 100 mg/mL, still more preferably not less than 120 mg/mL, and yet more preferably not less than 150 mg/mL. It should be noted that a liquid formulation containing antibody at a concentration of 120 mg/mL or higher, or preferably 150 mg/mL or higher, has not been developed for commercial use” with the “highest concentration of antibody in the liquid formulation according to the present invention may be typically 300 mg/mL, preferably 250 mg/mL and more preferably 200 mg/mL. Therefore, the antibody-containing liquid formulation according to the present invention preferably has an antibody concentration of from 50 to 300 mg/mL, more preferably from 100 to 300 mg/mL, still more preferably from 120 to 250 mg/mL, and yet more preferably from 150 to 200 mg/mL”, see paragraphs 0041-0042. This meets the limitations of instant claims 1 and 23 wherein the concentration of the anti-Aβ protofibril antibody is 80 mg/mL to 300 mg/mL, instant claims 2, 3, 4, 24, 25, 26, 33, 34, 35 wherein the concentration of the anti-Aβ protofibril antibody is 100 mg/mL to 200 mg/mL, instant claim 11 wherein the concentration of the anti-Aβ protofibril antibody is 80 mg/mL to 240 mg/mL, and instant claim 12 wherein the concentration of the anti-Aβ protofibril antibody is 80 mg/mL to 120 mg/mL.
Morichika et al. found that “in solutions in which a high concentration of antibody was dissolved a buffer solution containing the amino acid arginine, the amount of generated dimer was smaller than that in solutions to which arginine was not added. From these results, it was found that arginine is effective as a stabilizer for inhibiting dimerization. Further, in solutions in which a high concentration of antibody was dissolved in a buffer solution containing arginine and methionine, the inhibitory effect against dimerization was observed at a total concentration of arginine and methionine which is lower than the concentration of arginine alone needed for attaining the same inhibitory effect. From these results, it was found that a synergistic effect is obtained by the addition of arginine and methionine in combination”, see paragraph 0059. Morichika et al. found that an effective concentration for the “arginine concentration is 100 to 300 mM, and the methionine concentration is 10 to 50 mM”, see paragraph 0062. This meets the limitations of instant claim 1 wherein the arginine concentration is 100 mM to 400 mM, instant claim 5 wherein the formulation comprises methionine, instant claim 8 wherein the arginine concentration is 125 mM to 350 mM, instant claims 9 and 10 wherein the arginine concentration is 200 mM, instant claim 11 wherein the arginine concentration is 140 mM to 260 mM, instant claim 12 wherein the arginine concentration is 240 mM to 360 mM, instant claim 32 wherein the formulation comprises arginine, and instant claims 33, 34, 35 wherein the arginine concentration is 190 mM to 210 mM.
Morichika et al. teaches the use of polysorbate 80 as surfactants and stabilizers in the formulation wherein the concentration “is generally 0.0001 to 10% (w/v), preferably 0.001 to 5%, more preferably 0.005 to 3%”, see paragraph 0068. This meets the limitations of instant claim 1 wherein the polysorbate is at 0.01% w/v to 0.1% w/v, instant claim 11 wherein the polysorbate is at 0.02% w/v to 0.08% w/v, instant claim 12 wherein the polysorbate is at 0.02% w/v to 0.08% w/v, instant claim 33 wherein the polysorbate is at 0.04% w/v to 0.06% w/v, instant claim 34 wherein the polysorbate is at 0.05% w/v, and instant claim 35 wherein the polysorbate is at 0.05% w/v.
Morichika et al. teaches that the high concentration antibody formulation can have a pH range from 4 to 8, with more preferable embodiments including buffer solutions ranging from “5.0 to 7.5… A buffering agent which can be used in the present invention is one which can adjust the pH in this range and which is pharmaceutically acceptable”, see paragraph 0063. This meets the limitations of instant claims 1, 11, 12, 22, 33, 34, 35 wherein the pH ranges from 4.5 to 5.5.
Morichika et al. teaches “the high concentration antibody-containing liquid formulation according to the present invention, the buffer is preferably a histidine buffer or glycine buffer, and a histidine buffer is especially preferred. The concentration of the buffer solution is generally 1 to 500 mM, preferably 5 to 100 mM, still more preferably 10 to 20 mM”, see paragraph 0063. This meets the limitations of instant claims 1 and 23 wherein the formulation contains a pharmaceutically acceptable buffer, instant claims 7, 22, 27 wherein the histidine buffer is 10 to 100 mM, instants claims 10, 29, 34, 35 wherein the histidine buffer is 25 mM, instant claims 11, 28, 33 wherein the histidine buffer is 15 to 35 mM, instant claims 30 and 31 wherein the buffer is a histidine buffer.
It would be obvious at the time of the instant invention to use the high concentration of the anti-Aβ protofibril antibody known as “BAN2401” taught by Luthman et al., which is an antibody used as a treatment that results in the reduction of amyloid beta plaques related to Alzheimer’s Disease, with the formulation optimized for high concentration antibodies taught by Morichika et al., which uses routine optimization to find a suitable formulation for antibodies when they are needed for intravenous or subcutaneous administration. One would be motivated to combine the antibody with the formulation with the expectation of creating a “liquid formulation containing a high concentration of an antibody … with which reformulation by concentration by lyophilization is not necessary, and hence does not require reconstitution. The antibody-containing liquid formulation according to the present invention can be stored in a liquid state for a long time. Since the antibody-containing liquid formulation according to the present invention can be produced by a process not including a lyophilization step, addition of a sugar or the like as a cryoprotective agent is not necessary”, see paragraph 0030 of Morichika et al. This ensures the longevity of the antibody in formulation, success and ease of its administration to human subjects at high concentrations, and addresses common concerns of storing high concentration antibody formulations such as protein aggregation and protein loss overtime in varying conditions.
Therefore, claims 1-5, 7-12, and 22-35 are rejected as obvious over Luthman et al. and Morichika et al.
Response to Arguments
Applicant's arguments filed 02/02/2026 have been fully considered but they are not persuasive.
Applicant argues “one of ordinary skill in the art would understand that the particular formulation effective to stabilize lecanemab at high concentration could only be identified after bespoke evaluation and could not be predicted a priori merely by considering the formulation used with another antibody”. This is not found persuasive.
This argument is not persuasive because optimization of a pharmaceutical formulation for an antibody (e.g., modification of pH or excipient concentration) is considered routine and conventional within the art, and the argument that modification of the formulation renders the instant formulation distinct from the formulation of the prior art is not persuasive for nonobviousness. It would have been obvious to the ordinary artisan to modify the composition to improve antibody stability and decrease viscosity because it was already known that such changes could be advantageous when preparing pharmaceutical compositions for antibodies. One of ordinary skill in the art would argue that the stability observed after modification and optimization of the composition was expected, especially in the view of the art recognized need to develop stable antibody formulations and to modify the formulation to provide the best stability for a specific antibody through routine optimization. Modifying the composition to reach this endpoint is a part of routine optimization.
Additionally, there is sufficient teaching and guidance in the prior art at the time of filing for one of ordinary skill in the art to experimentally arrive at the claimed values from the ranges taught by the prior art. The limitations recited in the instant claims are predictable because the art teaches the rationale behind each addition to the formulation, which a skilled artisan can adjust depending upon the structure and identity of a particular antibody. The prior art teaches ranges for each of the additions to the formulations, which encapsulates the fact that the art recognizes that there needs to be adjustments made to formulations to adapt to the unique requirements of specific antibodies based on amino acid compositions. The prior art disclosures themselves speak to the fact that formulations are not static and depend on multiple factors to achieve the conditions a specific protein requires to be stable in an aqueous formulation. As such, certain endpoints, such as percentage of protein fragmentation, could be routine experimented for and determined based on the existing guidance within the prior art.
The instant claims are drawn to a composition and as such, the combination of references from the prior art address each of the components of the composition and render it obvious. The prior art describes broader ranges for the components of the formulation, and a skilled artisan can experiment to obtain certain values dependent upon their end target.
Applicant argues “a skilled artisan would have no expectation that the formulation of Morichika – optimized for a humanized anti-IL-6 receptor antibody—would stabilize an entirely unrelated antibody like lecanemab”. This is not found persuasive.
As discussed above, it is considered routine and conventional in the prior art to modify a composition based on the individual characteristics of the proteins of an antibody. The prior art references teach a range of conditions for the formulations and provide teachings on how one of ordinary skill in the art can modify the formulations accordingly to a desired end goal. This experimentation to derive a narrower value from a broader range is considered routine in the art. 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).
Applicant argues “Morichika certainly does not suggest that histidine provides unexpected stability benefits for lecanemab relative to other known stabilizing excipients”. This is not found persuasive.
Morichika et al. teaches the addition of histidine to the formulation as a way of maintaining the stability of the monoclonal antibody in a stable pH. One of ordinary skill in the art recognizes that histidine is included in many monoclonal antibody formulations, particularly high concentration formulations, to prevent protein aggregation, reduce viscosity, and offer cryo-protection in lyophilized products. While Morichika et al. does not explicitly teach that the concentration of histidine disclosed purports “unexpected benefits” over other potential stabilizers, it is clear that the taught ranges would confer the same characteristics in formulation since there is no evidence to the contrary. Thus, the burden is on the Applicant to demonstrate how the claim limitation, which is the same as what is taught in the prior art, 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. Currently, there is no evidence that the addition of histidine in the claimed formulation shows unexpected results compared to the addition of histidine in the formulation of the prior art.
As such, the rejection is maintained as obvious over Luthman et al. and Morichika et al.
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.
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/SELAM BERHANE/Examiner, Art Unit 1675
/AURORA M FONTAINHAS/Primary Examiner, Art Unit 1675
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