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 .
Applicant’s amendments and remarks filed 7-6-26 are acknowledged.
Upon reconsideration, the requirement that applicant elect a species of method step “wherein the UF/DF filtration buffer does not comprise β-cyclodextrin, rather β-cyclodextrin is added to the filtration pool subsequent to UF/DF” as opposed to a method step “wherein the UF/DF filtration buffer does comprise β-cyclodextrin” has been withdrawn.
Claims 1, 3-5, 8-12, 14-16 and 18 are pending and under examination as they read on:
the species of method “wherein the first binding domain of the bispecific molecule of claim 1 binds to CD19 or CD33,” and
the species of method “wherein the CD19-binding domain comprises the CDR sequences set out in claim 18(a), and wherein the CD33-binding domain comprises the CDR sequences set out in claim 18(b).”
The prior rejection under 35 U.S.C. 112(b) has been withdrawn in view of applicant’s claim amendments.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claim(s) 1, 4-14 and 18 stand rejected under 35 U.S.C. 103 as being unpatentable over Raum et al. (20170218078, of record) in view of Kanapuram et al. (20170209571, of record, hereinafter “Kana”).
Claim 3 stands rejected under 35 U.S.C. 103 as being unpatentable over Raum et al. (20170218078, of record) in view of Kanapuram et al. (20170209571, of record, hereinafter “Kana”) as applied to claims 1, 4-14 and 18 above, and further in view of Wang et al. (20130336957, of record).
Claim(s) 15 and 16 stand rejected under 35 U.S.C. 103 as being unpatentable over Raum et al. (20170218078, of record) in view of Kanapuram et al. (20170209571, of record, hereinafter “Kana”) as applied to claims 1, 4-14 and 18 above, and further in view of Callahan et al. (WO2019199476, of record).
Applicant argues Raum fails to teach “Adding β-Cyclodextrin During or After UF/DF” and that Kana fails to suggest doing so for a variety of reasons.
First, applicant argues Kana’s “entire inventive contribution is directed to a pH adjustment step before UF/DF to reduce post-UF/DF aggregation,” and that “Kanapuram’s mention of cyclodextrin is limited to a passing reference within a long, undifferentiated list of ‘stabilizing agents’ classified as ‘polymers.’ Kanapuram lists ‘cyclodextrin and derivatives thereof (e.g., hydroxypropyl-betacyclodextrin, sulfobutylether-beta-cyclodextrin)’ as one item among dozens of polymers in a general stabilizer enumeration. Kanapuram does not: (i) teach adding β-cyclodextrin to a UF/DF buffer or pool; (ii) specify any concentration of β-cyclodextrin; (iii) define any timing window for cyclodextrin addition relative to UF/DF; or (iv) demonstrate any experimental efficacy of cyclodextrin for preventing protein aggregation during downstream processing.
A bare mention in a laundry list of potential stabilizers does not constitute a teaching or suggestion to specifically select β-cyclodextrin and apply it in a UF/DF processing context
at defined concentrations and within a defined time window. A person of ordinary skill would
have had no reason to single out cyclodextrin from among the dozens of listed stabilizers in
Kanapuram and apply it specifically in a UF/DF buffer or pool, particularly because
Kanapuram's own inventive method relies on pH adjustment, not cyclodextrin addition.”
Applicant's arguments have been considered but have not been found convincing essentially for the reasons of record as described below.
By contrast to applicant’s argument the clear thrust of the “inventive contribution” of Kana is the use of β-cyclodextrins, and in particular, the particular β-cyclodextrin which is sulfobutylether-β-cyclodextrin (“SBE-β-CD”), to stabilize protein formulations so as to reduce aggregation and denaturation.
For example, the first few paragraphs of the "Summary" and "Detailed Description" sections of a patent application typically describe that which applicant considers new with respect to their technology, i.e., their “inventive contribution” are as follows:
“[0006] Preserving protein stability and activity in biological and biotechnological applications poses serious challenges. There is a need in the art for optimized pharmaceutical compositions that provide for enhanced stabilization of therapeutic proteins and reduce aggregation and denaturation during formulation, filling, shipping, storage and administration, thereby preventing loss-of-function and adverse immunogenic reactions. It is the object of the present invention to comply with thus need.
SUMMARY
[0007] Protein instability, and in particular protein aggregation, is an increasing challenge in the biotechnology industry, where aggregation is encountered throughout the lifetime of a therapeutic protein, including during refolding, purification, sterilization, shipping, and storage processes. It is thus the object of the present invention to provide a stable pharmaceutical composition comprising a bispecific single chain antibody construct, binding to a target cell surface antigen via a first binding domain and to the T cell surface antigen CD3 via a second binding domain; a β-cyclodextrin; and a buffer.
[0008] The β-cyclodextrin may be present in a selected from the group consisting of β-cyclodextrin, methyl-β-cyclodextrin, hydroxyethyl-β-cyclodextrin, hydroxypropyl-β-cyclodextrin, ethyl-β-cyclodextrin, butyl-β-cyclodextrin Succinyl-(2-hydroxypropyl)-β-cyclodextrin, heptakis(2,3,6-tri-O-methyl)-β-cyclodextrin, heptakis(2,3,6-tri-O-benzoyl)-β-cyclodextrin, β-cyclodextrin phosphate sodium salt, β-cyclodextrin sulphate sodium salt, triacetyl-β-cyclodextrin, heptakis(6-O-sulfo)-β-cyclodextrin heptasodium salt, carboxymethyl-β-cyclodextrin sodium salt, sulfobutylether-β-cyclodextrin sodium salt, 6-O-β-toluenesulfonyl-β-cyclodextrin, and in particular from sulfobutylether-β-cyclodextrin sodium salt, hydroxypropyl-β-cyclodextrin. It may be present in a concentration in the range of 0.1% to 20% (w/v), preferably of 0.5% to 2% (w/v) and more preferably of 0.8% to 1.5% (w/v).”
See also:
“DETAILED DESCRIPTION
[0036] Despite the high quality of current therapeutic biotech products and the resemblance of recombinant human proteins and antibodies to endogenous human proteins, protein instability remains an important concern. In addition to the quality-related consequences of protein aggregation such as possible loss of protein activity and undesirable aesthetics of drug product, soluble protein aggregates have been reported to have significant cytotoxic effects, and, importantly, are a potential risk factor for the development of an the immune response to protein products.
[0037] Protein aggregation can occur during at various points throughout the lifetime of a protein, including fermentation, refolding, purification, filling, shipment, storage or administration and is strongly dependent on various environmental factors. There is a critical need in the art to increase stability and reduce aggregation of therapeutic proteins; and optimized pharmaceutical formulations can aid in doing so. The present inventors investigated the effects of different cyclodextrins to on the aggregation of bispecific antibody constructs (specifically, Bi-specific T-cell engagers, BiTE®) when exposed to various environmental stress factors. Surprisingly, the inventors found that antibody constructs could be significantly stabilized in the presence of cyclodextrins, and in particular β-cyclodextrins.
[0038] Thus, the present invention provides a stable pharmaceutical composition comprising a) a bispecific single chain antibody construct, binding to a target cell surface antigen via a first binding domain and to the T cell surface antigen CD3 via a second binding domain, b) a β-cyclodextrin and c) a buffer.”
(emphasis added)
Additional emphasis on the use of SBE-β-CD, in particular, in a pharmaceutical composition comprising a bispecific single chain antibody construct of the invention is set forth at paras 14 and 138 of Kana (emphasis added):
“[0014] Also provided herein is a pharmaceutical composition free of preservatives, comprising a bispecific single chain antibody construct having the amino acid sequence of SEQ ID NO: 100 or 110 and being in a concentration of about 0.5 mg/ml, and further a cyclodextrin being sulfobutylether-β-cyclodextrin sodium salt in a concentration of about 1% (w/v), and further a buffer being potassium phosphate in concentration of about 10 mM, said formulation further comprising sucrose in concentration of about 8% (w/v) of and polysorbate 80 in concentration of about 0.01% (w/v) at a pH of about 6.0.”
“[0168] However, it is also conceivable that the pharmaceutical composition does not comprise any preservatives. In particular, the present invention inter alia provides a pharmaceutical composition being free of preservatives, comprising a bispecific single chain antibody construct having an amino acid sequence as depicted in SEQ ID Nos. 100 and 110 in a concentration of about 0.5 mg/ml, sulfobutylether-β-cyclodextrin sodium salt in a concentration of about 1% (w/v), and potassium phosphate in concentration of about 10 mM, and further sucrose in concentration of about 8% (w/v) of and polysorbate 80 in concentration of about 0.01% (w/v) at a pH of about 6.0.”
Moreover, the use of β-cyclodextrin as a bispecific single chain antibody construct formulation stabilizing agent is featured throughout the majority of the working examples, such as in Examples 3-15. Further in this regard, see the prior Office Action at page 19, 1st paragraph, “Additionally, the ability of various β-cyclodextrins such as HP-β-CD and SBE-β-CD to mitigate various other stresses to bispecific antibody formulations is disclosed in Example 1 (temperature induced stress), Example 2 (surface induced stress conditions caused by, e.g., successive freezing and thawing cycles as well as foaming effects), Examples 3 and 4 (aggregation stress caused by the anti-microbial Formulation additive benzyl alcohol), Example 5 (storage-induced stress due to six days at 37 C), Example 7 (Liquid-Liquid Phase Separation (LLPS) stress), and others (Examples 8 and 11).”
Thus, by contrast to applicant’s argument it remains the opinion of the undersigned that the clear thrust of the “inventive contribution” of Kana is the use of β-cyclodextrins, and in particular, the particular β-cyclodextrin which is sulfobutylether-β-cyclodextrin (“SBE-β-CD”), to stabilize protein formulations so as to reduce aggregation and denaturation.
More particularly, as set forth in the prior Office Action at page 19, final full paragraph through page 19-20 bridging paragraph, the claimed in invention was obvious in view of the teachings of Raum in view of Kana:
“Given the teachings of Raum in view of Kana it would be obvious to the ordinarily skilled artisan wishing to make CD19xCD3 HLE construct, e.g., a CD19-binding, AMG103-based x CD3-binding bispecific, or a CD33xCD3 HLE construct, e.g., a CD33-binding, AMG330-based x CD3-binding bispecific, either of said bispecific constructs comprising the scFc HLE moiety, by a process that involves a UF/DF purification + buffer exchange step that a β-cyclodextrin, such as HPBCD or SBE-β-CD, should be added to the post-UF/DF product pool in the presence of a polysorbate, such as polysorbate 80, and a sugar, such as sucrose, wherein the post-UF/DF product pool has a pH around 6.0, so as to minimize the formation of HMWS.
More particularly, given the reference teachings set forth above it would likewise have been obvious to one of ordinary skill in the art that wherein the CD19xCD3 HLE or the CD33x CD3 HLE constructs, each comprising the scFc HLE moiety, is subjected to downstream purification via ultrafiltration / diafiltration (UF/DF), the ordinarily skilled artisan would clearly understand that the post-UF/DF product pool is an appropriate stage to ensure the bispecific CD19xCD3 HLE / CD33x CD3 HLE constructs will be stable under various stressors such as freeze thaw stress (Raum Example 10), or storage at -20 C for 6 weeks (Kana Example 12), and thus this is likewise an appropriate time to ensure that stabilizing agents such as HPBCD / SBE-β-CD, polysorbate 80 and sucrose are present.”
Turning to applicant’s arguments in Section 3 of their remarks filed 7-6-26 about the allegedly “unexpected results,” applicant asserts:
“…it was a surprising finding that β-cyclodextrin, and specifically SBE-β-CD, could effectively stabilize bispecific antigen-binding molecules during downstream processing, which is a fundamentally different stress environment from that of static storage formulations. The specification explicitly notes that protein stress conditions in downstream processing differ from static formulation conditions: in downstream processing, stress originates from shear stress as process fluids are in motion and column, tube, and other interfaces provide many opportunities for protein aggregation, whereas in storage formulations, stress originates primarily from temperature, light, and container surfaces.”
Applicant's argument has been considered but has not been found convincing essentially for the reasons of record as described below.
By contrast to applicant’s argument the ordinarily skilled artisan would not have been surprised that β-cyclodextrin, and specifically SBE-β-CD, could effectively stabilize bispecific antigen-binding molecules during the UF/DF step or thereafter.
For example, at para 45 Kana teaches (emphasis added):
“[0045]…Advantageously, the pharmaceutical compositions of the invention are envisaged to be stable, i.e. to remain free or substantially free from protein aggregates even when subjected to stress, in particular thermal stress, storage, surface-induced stress (such as freeze/thaw cycles, foaming), concentration (by ultra- and diafiltration) or being mixed with organic compounds such as antimicrobial preservatives. Preferably, the pharmaceutical compositions may have similar or even improved characteristics as compared to the compositions comprising SBE-β-CD or HP β-CD that have been evaluated in the appended Examples. Pharmaceutical compositions of the invention are preferably homogenous solutions of dispersed monomeric bispecific single chain antibody constructs.”
Moreover working Example 8 Kana describes “Buffer Exchange and Protein Concentration of AMG 330 by Ultrafiltration Centrifugation in the Presence of 4 Different Formulations (Including SBE-β-CD),” and concludes:
“[t]he presence of SBE-β-CD appears to provide significant protection to AMG 330 against the formation of HMW during protein concentration by ultrafiltration with the lowest relative amount of aggregates in formulation containing SBE-β-CD….”
(see Example 8, including para 215, emphasis added).
Moreover, applicant’s more specific argument that “[i]t was particularly surprising that the addition of β-cyclodextrin had to be performed within a defined time period, typically within 24 hours, even more preferred within 10 hours, after the end of the UF/DF step, and more preferably immediately after the end of the UF/DF step, in order to keep aggregate formation low” was likewise not found convincing.
By contrast to applicant’s argument, the teachings of Kana at Example 8 would suggest to the skilled artisan that “Captisol,” a.k.a., “SBE-β-CD,” can effectively protect bispecific antigen-binding molecules from aggregate formulation both during and after the UF/DF process, per se, where shear stress occur when process fluids are in motion across column, tube, or other interfaces associated therewith.
Thus, the skilled artisan would not be surprised, e.g., that addition of SBE-β-CD can effectively protect bispecific antigen-binding molecules from aggregate formulation when added to the filtration buffer that is being used in the course of UF/DF as described above, or that the presence of SBE-β-CD in the final filtration buffer / the final formulation buffer stabilizes bispecific antigen-binding molecules in the context of aggregation stress caused by the anti-microbial formulation additive benzyl alcohol; storage-induced stress due to six days at 37 C; Liquid-Liquid Phase Separation (LLPS) stress; and the levels of aggregation measured after 1-4 days incubation at 4° and 25° C (see, e.g., Kana Examples 3-5 and 11, respectively).
In conclusion, when Applicant’s arguments are taken as a whole and weighed against the evidence supporting the prima facie case of unpatentability, the instant claims, by a preponderance of evidence, remain unpatentable. See M.P.E.P. §§ 716.01(d) and 2142.
No claims are allowed.
THIS ACTION IS MADE FINAL. 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 ZACHARY S SKELDING whose telephone number is (571)272-9033. The examiner can normally be reached M-F 9-5 EST.
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/ZACHARY S SKELDING/Primary Examiner, Art Unit 1644
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