DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Status of the Claims
Claims 1-14, 18-25, and 35-37 have been cancelled. Claims 39-40 have been withdrawn. Claims 15-17, 26-34, and 38 have been amended. Therefore, claims 15-17, 26-34, and 38 are pending and currently under examination (claim set filed 07/16/2025).
Withdrawal of Rejections
The response and amendments filed on 07/16/2025 are acknowledged. Any previously applied minor objections and/or minor rejections (i.e., formal matters), not explicitly restated here for brevity, have been withdrawn necessitated by Applicant’s formality corrections and/or amendments. For the purposes of clarity of the record, the reasons for the Examiner’s withdrawal, or maintaining, if applicable, of the substantive or essential claim rejections are detailed directly below and/or in the Examiner’s Response to Arguments section.
Briefly, the previous claim rejections under 35 U.S.C. 112(b) for indefiniteness have been withdrawn necessitated by Applicant’s amendments. The previous claim rejections under 35 U.S.C. 101 for subject matter eligibility have been withdrawn necessitated by Applicant’s cancellation of claims and amendments.
The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application.
Maintained Rejections
Claim Rejections - 35 USC §103, Obviousness
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 15-17, 26-31, 33-34, and 38 are rejected under 35 U.S.C. 103 as being unpatentable over Rummel (EP 2524963; Date of Publication: November 21, 2012 – cited in the IDS filed on 01/04/2023 – previously cited) in view of Hunt (US Patent No. 8,137,677; Date of Publication: March 20, 2012 – cited in the IDS filed on 01/04/2023 – previously cited) and Gadgil (Identification of cysteinylation of a free cysteine in the Fab region of a recombinant monoclonal IgG1 antibody using Lys-C limited proteolysis coupled with LC/MS analysis; 2006 – previously cited).
Rummel’s general disclosure relates to “a novel proteolytically active polypeptide” (see, e.g., Rummel, abstract), wherein the “proteolytically active polypeptide is capable of hydrolysing botulinum or tetanus neurotoxin to produce di-chain botulinum or di-chain tetanus neurotoxin” (see, e.g., Rummel, [0008]). Moreover, Rummel discloses the generation of an active di-chain BoNT/A protein through the use of Lys-C protein (see, e.g., Rummel, [0003], [0006], [0010], [0049]).
Regarding claim 15(a) pertaining to an active di-chain BoNT/A protein, Rummel teaches the production of an active di-chain BoNT/A protein (see, e.g., Rummel, [0003], [0006], [0010]). Moreover, Rummel teaches the use of Lys-C for proteolytically processing polypeptides to produce active di-chain BoNT/A (see, e.g., Rummel, [0049]). Claim 15(a) is a product-by-process claim; therefore, patentability of a product does not depend on its method of production (see, e.g., MPEP 2113). Furthermore, for the purposes of applying prior art, prior art will be applied to the active di-chain BoNT/A protein.
Regarding claim 15(i) pertaining to less than 2% single-chain BoNT/A, Rummel teaches a composition that comprises “a mixture of processed and unprocessed second polypeptide, wherein said mixture may contain less than 5%, 4%, 3%, 2% or less than 1% unprocessed second polypeptide” (see, e.g., Rummel, [0066]), wherein the “unprocessed second polypeptide” can be single-chain BoNT/A.
Regarding claims 15(ii)-16, and 26-30 pertaining to the concentration of BoNT/A, Rummel teaches 100 ng of BoNT/A (see, e.g., Rummel, [0011]).
Regarding claim 15(c) pertaining to water, Rummel teaches that water may be used as a carrier (see, e.g., Rummel, [0071]).
Regarding claim 17 pertaining to the buffer, Rummel teaches “100 mM Tris-HCl, pH 8.0 or PBS (50 mM Na2HPO4, 150 mM NaCl, pH 7.4)” (see, e.g., Rummel, [0011]).
Regarding claim 17 pertaining to sodium chloride, Rummel teaches the use of sodium chloride (i.e., NaCl) in buffers (see, e.g., Rummel, [0054]).
Regarding claims 17 and 33 pertaining to the disaccharide, Rummel teaches sucrose and lactose (see, e.g., Rummel, [0071]).
Regarding claim 34 pertaining to the buffer concentration, Rummel teaches 50 mM disodium phosphate (see, e.g., Rummel, [0011]).
However, Rummel does not teach: wherein the Lys-C concentration is less than 400 pg (claims 15-16, and 26-30); or wherein the liquid pharmaceutical composition comprises a non-ionic surfactant that is a polysorbate or poloxamer (claims 15 and 31); or wherein the liquid pharmaceutic composition does not comprise a protein stabilizing agent (claim 15); or wherein the liquid pharmaceutical composition comprises sterile water (claim 17); or wherein the active di-chain BoNT/A protein remains stable at 25oC for at least 12 weeks (claim 38).
Hunt’s general disclosure relates to “A Clostridial toxin pharmaceutical composition comprising a Clostridial toxin, such as a botulinum toxin, wherein the Clostridial toxin present in the pharmaceutical composition is stabilized by a non-protein excipient such as a polyvinylpyrrolidone, a disaccharides, a trisaccharide, a polysaccharide, an alcohol, a metal, an amino acid, a surfactant and/or a polyethylene glycol” (see, e.g., Hunt, abstract). Moreover, Hunt discloses that the pharmaceutical composition containing at least one active ingredient (such as a Clostridial toxin), one or more excipients, buffers, carriers, stabilizers, preservatives, and/or bulking agents, is suitable for administration to a patient to achieve a desired diagnostic result or therapeutic effect (see, e.g., Hunt, [3]).
Regarding claims 15 and 31 pertaining to a non-ionic surfactant, Hunt teaches polysorbate (Tween), which is a non-ionic surfactant (see, e.g., Hunt, [79]).
Regarding claim 15 pertaining to the composition not comprising a protein stabilizing agent, Hunt teaches a non-protein stabilizing agent, such as polyvinylpyrrolidone, disaccharides, trisaccharide, a polysaccharide, an alcohol, a metal, an amino acid, a surfactant and/or a polyethylene glycol (see, e.g., Hunt, abstract).
Regarding claim 17 pertaining to sterile water, Hunt teaches the use of sterile water as an excipient (see, e.g., Hunt, [23]).
Regarding claim 38 pertaining to stability, Hunt teaches that the botulism neurotoxin formulation is stable for at least 6 months at temperatures between 10-30oC (see, e.g., Hunt, [30]).
Gadgil’s general disclosure pertain to proteolysis of MAB007 with Lys-C (see, e.g., Gadgil, abstract). Moreover, Gadgil discloses the use of Lys-C due to its ability to induce limited proteolysis in order to characterize chemical modifications with the MAB007 protein (see, e.g., Gadgil, Introduction, pg. 166).
Regarding claims 15-16, and 26-30 pertaining to the Lys-C concentration being less than 400 pg, Gadgil teaches that the protein/Lys-C enzyme ratio is 400:1 (see, e.g., Gadgil, Materials and Methods – Limited Proteolysis, pg. 167). This ratio results in a concentration that is less than 400 pg Lys-C when 100 ng BoNT/A protein is present, as taught by Rummel.
Regarding claims 15-16, and 26-30’s concentration limitations, MPEP 2144.05 states that “Generally, differences in concentrations or temperatures will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. Where the general conditions of a claims are disclosure in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation”. Those working in the biological and/or pharmaceutical arts would understand that the adjustments of particular conventional working conditions (e.g., concentration or amount of a compound) is deemed a matter of judicious selection and routine optimization, which is within the purview of the skilled artisan. For example, the disclosure of Gadgil states that the protein/enzyme ratio of 400:1 results in partial cleavage of the protein (see, e.g., Gadgil, Materials and Methods – Limited Proteolysis, pg. 167). Moreover, Rummel teaches that the amount of proteolytically active polypeptide can be modified (see, e.g., Rummel, [0011]). Additionally, Rummel states that “those skilled in the art will be able to determine operative and optimal assay conditions for each determination by employing routine experimentation (see, e.g., Rummel, [0044]). Therefore, one of ordinary skill in the art would reasonably understand that the amount of BoNT/A and Lys-C influences the amount of proteolytic cleavage to form an active di-chain BoNT/A protein. This is motivation for someone of ordinary skill in the art to practice or test the parameter widely to find those that are functional or optimal which then would be inclusive or cover the steps as instantly claimed. Absent any teaching of criticality by the Applicant concerning concentration, it would be prima facie obvious that one of ordinary skill in the art would recognize these limitations are results effective variable which can be met as a matter of routine optimization.
It would have been first obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to add a non-ionic surfactant, as taught by Hunt, to Rummel’s BoNT/A protein composition. One would have been motivated to do so because Hunt teaches that a surfactant, such as polysorbate, is a non-protein stabilizing agent for pharmaceutical compositions that comprise Clostridial toxins (see, e.g., Hunt, abstract). Moreover, Rummel teaches the production of a composition comprising an active di-chain BoNT/A protein (see, e.g., Rummel, [0003], [0006], [0010], [0049]). Therefore, based on the teachings of Rummel and Hunt, it would have been obvious to add a surfactant to a composition comprising an active di-chain BoNT/A protein because the non-ionic surfactant would stabilize the active BoNT/A protein.
It would have been secondly obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to add sterile water, as taught by Hunt, to Rummel’s BoNT/A protein composition. One would have been motivated to do so because Hunt teaches that addition of the proteolytically active BoNT/A and non-protein excipients to the sterile water can allow for the formation of a sterile BoNT/A solution (see, e.g., Hunt, [23]). Moreover, Rummel teaches the production of a composition comprising an active di-chain BoNT/A protein, wherein the composition can be administered as a medicament (see, e.g., Rummel, [0003], [0006], [0010], [0049], [0068]). Therefore, based on the teachings of Rummel and Hunt, it would have been obvious to add sterile water to the composition comprising the proteolytically active BoNT/A protein in order to produce a composition that can be sterile and administered as a medicament.
It would have been thirdly obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to produce Rummel’s BoNT/A protein composition with stability for at least 6 months at temperatures between 10-30oC, as taught by Hunt. One would have been motivated to do so because Hunt teaches “stabilizing nontoxic proteins dissociate from the neurotoxin, resulting in a gradual loss of toxicity, particularly as the pH and temperature rise” (see, e.g., Hunt, [29]). Moreover, Hunt teaches that a surfactant, such as polysorbate, is a non-protein stabilizing agent for pharmaceutical compositions that comprise Clostridial toxins (see, e.g., Hunt, abstract). Furthermore, Rummel teaches the production of a composition comprising an active di-chain BoNT/A protein (see, e.g., Rummel, [0003], [0006], [0010], [0049]). Therefore, based on the teachings of Rummel and Hunt, it would have been obvious to produce a composition comprising an active di-chain BoNT/A protein, wherein the composition is stable for a specific amount of time at a specific temperature. One would have expected success because Hunt and Rummel both teach BoNT/A compositions.
Claim 32 is rejected under 35 U.S.C. 103 as being unpatentable over Rummel, Hunt, and Gadgil as applied to claims 15-17, 26-31, 33-34, and 38 above, and further in view of Taylor (WO 2011/048044; Date of Publication: April 28, 2011 – previously cited).
The teachings of Rummel, Gadgil, and Hunt, herein referred to as modified-Rummel-Hunt-Gadgil, are discussed above as it pertains to a composition comprising an active di-chain BoNT/A protein.
However, modified-Rummel-Hunt-Gadgil does not teach: wherein the surfactant is present at a concentration of less than 1% v/v (claim 32).
Taylor’s general disclosure relates to “tools for the quality control and safety during manufacture of neurotoxins” (see, e.g., Taylor, abstract). Moreover, Taylor discloses “ In particular, it relates to a method for the determination of the amount of partially processed and/or unprocessed Botulinum neurotoxin A polypeptide (BoNT/A) in a solution comprising processed and partially processed and/or unprocessed BoNT/A comprising the steps of contacting a sample of said solution with a capture antibody which specifically binds to the partially processed and unprocessed BoNT/A under conditions which allow for binding of said antibody to said partially processed and unprocessed BoNT/A, whereby a complex is formed, and determining the amount of the formed complex, whereby the amount of the complex is indicative for the amount of the partially processed and/or unprocessed BoNT/A in said solution” (see, e.g., Taylor, abstract). Furthermore, Taylor discloses the addition of surfactant(s) to the composition during manufacturing in order to wash the BoNT/A proteins during the manufacturing process (see, e.g., Taylor, [0022]).
Regarding claim 32 pertaining to the concentration of surfactant, Taylor teaches that the surfactant “is present at a concentration in the range of 0.01 % (v/v) to 10% (v/v)” (see, e.g., Taylor, [0022]).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to produce modified-Rummel-Hunt-Gadgil’s BoNT/A protein composition with a surfactant present at a concentration in the range of 0.01 % (v/v) to 10% (v/v), as taught by Taylor. One would have been motivated to do so because Taylor teaches that these surfactant concentration(s) are used to wash the BoNT/A protein. Moreover, modified-Rummel-Hunt-Gadgil teaches that non-ionic surfactant(s) act as non-protein stabilizing agent for pharmaceutical compositions that comprise Clostridial toxins (see, e.g., Hunt, abstract). Therefore, based on the teachings of modified-Rummel-Hunt-Gadgil and Taylor, it would have been obvious to include a non-ionic surfactant into the composition comprising the BoNT/A protein because this would result in washing, and subsequent stabilization, of the active di-chain BoNT/A protein. One would have expected success because modified-Rummel-Hunt-Gadgil and Taylor both teach BoNT/A.
Maintained Rejection
Double Patenting
Claims 15-17, and 26-30 are rejected on the ground of non-statutory double patenting as being unpatentable over claims 1-11 of U.S. Patent No. 11,642,399.
Although the claims at issue are not identical, they are not patentably distinct from each other because US’399 teaches a liquid pharmaceutical comprising an active di-chain BoNT/A protein; Lys-C; a surfactant; and water; wherein: the composition does not comprise a protein stabilizing agent; the Lys-C is present at a concentration of less than 400 pg Lys-C per 100 ng BoNT/A protein; and less than 2% of the BoNT/A in the composition is single-chain BoNT/A (see, e.g., US’399, claim 1); wherein the composition contains Lys-C at a concentration of less than 300 pg Lys-C per 100 ng BoNT/A protein (see, e.g., US’399, claim 2); wherein the liquid pharmaceutical further comprises sodium chloride; a buffer with a pH between 5.5 and 7.5; a disaccharide; wherein the water is sterile water (see, e.g., US’399, claim 3); wherein the composition contains Lys-C at a concentration of less than 200 pg Lys-C per 100 ng BoNT/A protein (see, e.g., US’399, claim 4); wherein the composition contains Lys-C at a concentration of less than 100 pg Lys-C per 100 ng BoNT/A protein (see, e.g., US’399, claim 5); wherein the composition contains Lys-C at a concentration of less than 50 pg Lys-C per 100 ng BoNT/A protein (see, e.g., US’399, claim 6); wherein the composition contains Lys-C at a concentration of less than 20 pg Lys-C per 100 ng BoNT/A protein (see, e.g., US’399, claim 7); wherein the composition contains Lys-C at a concentration of less than 10 pg Lys-C per 100 ng BoNT/A protein (see, e.g., US’399, claim 8); wherein less than 1% of the BoNT/A in the composition is single-chain BoNT/A (see, e.g., US’399, claim 9); wherein the composition is produced using a method wherein a soluble single-chain BoNT/A protein is contacted with Lys-C in solution and, following such contact, the BoNT/A is separated from Lys-C by contacting the solution containing the BoNT/A and Lys-C with a hydrophobic surface, wherein the BoNT/A binds with preference to the hydrophobic surface (see, e.g., US’399, claim 10); and wherein the composition consists of BoNT/A protein wherein less than 2% of the protein is in single-chain form; a non-protein stabilizing agent that is a surfactant; water; Lys-C at less than 400 pg Lys-C per 100 ng BoNT/A protein; sodium chloride; a buffer to maintain pH between 5.5 and 7.5; and a disaccharide (see, e.g., US’399, claim 11).
Examiner’s Response to Arguments
Applicant’s amendments and arguments filed on 07/16/2025 have been fully considered but they are not persuasive and deemed insufficient to overcome the prior arts of record.
In response to Applicant’s argument that Gadgil contains no disclosure relating to BoNT/A and that there is no rationale for applying Gadgil’s proteolysis conditions for the concentration of Lys-C (remarks, page 7), this argument is not persuasive for multiple reasons. First, Gadgil was not used to teach BoNT/A, instead Rummel was used to teach the production of an active di-chain BoNT/A protein (see, e.g., Rummel, [0003], [0006], [0010]). Secondly, the broadest reasonable interpretation (BRI) of independent claim 15 pertains to a liquid pharmaceutical composition comprising an active di-chain BoNT/A protein, a non-ionic surfactant, and water. The contacting of the BoNT/A protein with Lys-C to produce an active di-chain BoNT/A protein is considered a product-by-process limitation and does not serve to further limit the composition of independent claim 15; therefore, any concentration limitation that teaches Lys-C serves to further limit the product-by-process limitation of the claim. However, for the purposes of compact prosecution, and since Lys-C is needed to produce the active BoNT/A protein, Gadgil was used to teach the concentration of Lys-C for the purposes of proteolysis. Moreover, Gadgil is considered analogous art to Rummel since Rummel teaches the use of Lys-C for proteolytically processing polypeptides to produce active di-chain BoNT/A (see, e.g., Rummel, [0049]). Thirdly, regarding the teachings of Gadgil, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Rummel teaches the production of an active di-chain BoNT/A protein and the use of Lys-C for proteolytically processing polypeptides to produce active di-chain BoNT/A (see, e.g., Rummel, [0049]). Moreover, Gadgil was used to teach the concentration of Lys-C for proteolytic processing of proteins (see, e.g., Gadgil, Materials and Methods – Limited Proteolysis, pg. 167). Therefore, one of ordinary skill in the art would have been motivated to combine the teachings of Rummel and Gadgil in order to have a concentration of Lys-C that is effective for proteolytic processing BoNT/A in order to produce an active di-chain BoNT/A protein.
In response to Applicant’s argument that one would have been motivated to increase the amount of Lys-C relative to BoNT/A (remarks, page 7), this argument is not persuasive for multiple reasons. First, Gadgil teaches that the protein/Lys-C enzyme ratio is 400:1 (see, e.g., Gadgil, Materials and Methods – Limited Proteolysis, pg. 167). This ratio results in a concentration that is less than 400 pg Lys-C when 100 ng BoNT/A protein is present, as taught by Rummel. Therefore, when the teachings of Rummel and Gadgil are taken together, one of ordinary skill in the art would have been motivated to employ a Lys-C concentration at or less than 400 pg. Secondly, as discussed above, MPEP 2144.05 states that “Generally, differences in concentrations or temperatures will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. Where the general conditions of a claims are disclosure in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation”. Therefore, the combined teachings of Rummel and Gadgil provide motivation for someone of ordinary skill in the art to practice or test the parameter widely (i.e., the concentration of Lys-C) to find those that are functional or optimal which then would be inclusive or cover the steps as instantly claimed. Thirdly, the Applicant has not provided any evidence that the concentrations of Lys-C claimed are critical to the claimed invention. Therefore, a prima facie obvious exists because these limitations are results effective variable which can be met as a matter of routine optimization.
In response to Applicant’s argument that Hunt does not contain any disclosure relating to Lys-C (remarks, page 8), this argument is not persuasive because Hunt was not used to teach the limitations pertaining to Lys-C, but instead Hunt was used to teach the limitation(s) pertaining to the stabilizing agents. The limitations pertaining to Lys-C were taught by Gadgil, as discussed above. Moreover, Hunt teaches the use of stabilizing agents in BoNT-containing compositions in order to stabilize botulinum toxin (see, e.g., Hunt, abstract). Therefore, Hunt is analogous art because the teachings of Hunt pertain to BoNT-containing compositions. Moreover, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
In response to Applicant’s argument that Rummel and Gadgil do not disclose the use of a surfactant in BoNT-containing compositions (remarks, page 8), this argument is not persuasive because Rummel and Gadgil were not used to teach the limitation pertaining to the use of a surfactant in BoNT-containing compositions. Taylor was used to teach the limitation(s) pertaining to surfactants, wherein Taylor teaches compositions containing neurotoxins, wherein surfactant “is present at a concentration in the range of 0.01 % (v/v) to 10% (v/v)” (see, e.g., Taylor, [0022]). Additionally, Taylor is analogous art because Taylor teaches compositions containing neurotoxins, which can include BoNT-containing compositions. Moreover, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
In response to Applicant’s argument that the non-statutory double patenting rejection has been obviated by the concurrently-filed Terminal Disclaimer (remarks, page 9), this argument is not persuasive because the Terminal Disclaimer filed on 07/16/2025 was not dissaproved on 07/22/2025. Therefore, the non-statutory double patenting rejection is maintained.
Conclusion
Claims 15-17, 26-34, and 38 are rejected.
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.
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/NATALIE IANNUZO/Examiner, Art Unit 1653
/NGHI V NGUYEN/Primary Examiner, Art Unit 1653