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
Claims 1-2 and 4-12 are pending and under examination on their merits. Claim 3 is cancelled.
Response to Arguments
Applicant's arguments filed 12/26/2025 have been fully considered but they are not persuasive.
Applicant argues against the rejection of claims under 35 U.S.C. 103 on the grounds that claim 3 was not previously rejected under 35 U.S.C. 103 and the limitation of claim 3 is now incorporated into amended claim 1, as well as claim 12, such that amended claims 1 and 12 are now likewise free of any rejections under 35 U.S.C. 103 (Arguments, second to last paragraph on page 15).
In response, this argument is not persuasive because claim 3 previously required a complex of botulinum toxin and protamine in a specific mass ratio, whereas amended claims 1 and 12 do not require that the botulinum toxin and the protamine sulfate form a complex in a mass ratio of 1:5 to 1:20. Rather, amended claim 1 specifies the mass ratio of botulinum toxin to protamine sulfate in the composition, not in the complex, and amended claim 12 requires mixing the toxin and protamine sulfate in a specific mass ratio but does not require a complex of botulinum toxin and protamine in a specific mass ratio.
Applicant argues that protamine sulfate has conventionally been regarded as an impurity and has been removed after purification steps of botulinum toxin (Arguments, page 16, paragraph 4).
In response, Applicant has not presented any objective evidence to support this point. Per MPEP 716.01(c)(II), Arguments by Applicant cannot take the place of evidence.
Applicant argues that the freeze-dried composition achieves surprising storage stability effects (Arguments, page 16, paragraph 5).
In order to establish that results are unexpected, the burden is on the applicant to establish results are unexpected and significant: “the evidence relied upon should establish that the differences in results are in fact unexpected and unobvious and of both statistical and practical significance” (MPEP 716.02(b) I). Here, Applicant has not met these criteria. Table 5 in [97] of the specification includes two test conditions (“Batch No.”): Comparative Example 9 and Example 4. However, the specification does not include a “Comparative Example 9” or an Example 9. It is unclear whether the two conditions in the table represent an average of three replicates or whether these are single experiments. Applicant has not presented any evidence of statistical significance of the results in the table. Therefore, the results presented are insufficient to overcome the rejection under 35 U.S.C. 103.
Applicant argues that Forssen teaches aqueous solutions containing the permeabilizing agent or the permeabilizing agent being added to rehydrate a lyophilized botulinum toxin ([9]), as opposed to protamine sulfate or another cationic surfactant or permeabilizing agent being freeze-dried or included as an ingredient of a freeze-dried composition (Arguments, page 17, paragraph 4).
In response, Forssen teaches the pharmaceutical composition can be prepared by lyophilization ([113]). The use of the word “composition” reads on the inclusion of other components besides the botulinum toxin, including the permeabilizing agent.
Applicant argues that Forssen teaches that other permeabilizing agents such as tyloxapol fail to achieve the intended effect (Arguments, bottom paragraph on page 18).
This argument is not persuasive because Forssen does not teach away from the use of protamine sulfate as a permeabilizing agent. Forssen’s teaching regarding tyloxapol do not pertain to the claimed invention.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
(New Rejection Necessitated by the Amendment) Claim 12 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 12 recites “(a) forming a complex of botulinum toxin and protamine sulfate by mixing botulinum toxin and protamine sulfate in a mass ratio of 1:5 to 1:20 (botulinum toxin: protamine sulfate).” This limitation renders the claim indefinite because it is unclear whether the parenthetical is a required feature or merely exemplary. Applicant may consider amending to the following to obviate this rejection: (a) forming a complex of botulinum toxin and protamine sulfate by mixing botulinum toxin and protamine sulfate in a mass ratio of 1:5 to 1:20 botulinum toxin to protamine sulfate.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
The following rejections are necessitated by the amendment.
Claims 1, 4, and 10-12 are rejected under 35 U.S.C. 103 as being unpatentable over Forssen (RU 2720991 C2) in view of Park (International Anesthesiology Clinics 42.3 (2004): 135-145.) and Gilsdorf et al. (Protein Expression and Purification 46 (2006) 256–267)
This rejection applies to the embodiment in which the botulinum toxin is serotype B light chain.
Claim 1 and its dependents are interpreted as a freeze-dried composition comprising a complex of botulinum toxin and protamine sulfate, an isotonic agent, and a buffering agent. The concentrations in claims 2 and 6-10 are interpreted as the concentration of each component in the composition before it is freeze-dried.
Forssen teaches a pharmaceutical composition comprising botulinum toxin and at least one permeabilizing agent containing a nonionic surfactant (Forssen claim 1), wherein the surfactant is present in an amount of from 0.01% to 0.5% w/v (Forssen claim 4). In one embodiment, the permeabilizing agent is a cationic surfactant that includes protamine sulfate ([89]). The permeabilizing agent may comprise human serum albumin ([94]). The permeabilizing agent selectively binds to a botulinum toxin to form a complex ([87]). The pharmaceutical composition may comprise buffers and tonicity control agents (“isotonic agent”) such as mannitol ([115]). The pharmaceutical composition can be prepared by lyophilization ([113]). Forssen teaches that the botulinum toxin is any of serotypes A, B, C, D, E, F, or G and the heavy or light chains thereof ([29]).
Forssen does not exemplify a freeze-dried composition comprising a complex of botulinum toxin and protamine sulfate, an isotonic agent, and a buffering agent, but a composition comprising a botulinum toxin, protamine sulfate, an isotonic agent (synonym for tonicity agent), and buffering agent is within the scope of Forssen’s disclosure. Furthermore, it would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine the composition of botulinum toxin and protamine sulfate with a buffering agent in order to maintain the pH of the composition and an isotonic agent in order to maintain the tonicity of the composition. The person of ordinary skill in the art would have had a reasonable expectation of success in combining components with art-recognized functions (tonicity agents and buffering agents).
Although Forssen teaches that in some embodiments the permeabilization agent complexes with the botulinum toxin ([87]) and also teaches that in some embodiments the permeabilization agent is protamine sulfate ([89]), Forssen does not explicitly teach that protamine sulfate forms a complex with the botulinum toxin or the pH at which this occurs.
Park teaches that protamine sulfate forms a complex with heparin because protamine is positively charged and heparin is negatively charged (Abstract). Protamine-heparin complexes have been demonstrated in vivo (Park, paragraph 2 on page 137).
Gilsdorf teaches that the isoelectric point (pI) of the native BONT/B light chain (LC) occurs at pH 6.3 (page 260, right column, Isoelectric focusing).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to formulate the composition of Forssen at a pH above the isoelectric point of botulinum toxin B light chain such that the botulinum toxin is negatively charged and complexes with positively charged protamine sulfate. The person of ordinary skill in the art would have been motivated by Forssen’s teaching that the permeabilizing agent (protamine sulfate) complexes with botulinum toxin as well as Park’s teaching of how protamine sulfate complexes with other molecules (i.e. by charge interactions). Furthermore, the person of ordinary skill in the art would have relied on Gilsdorf’s teaching of the isoelectric point of botulinum toxin B light chain (i.e. the pH at which botulinum toxin B light chain is negatively charged) to arrive at the claimed invention with a reasonable expectation of success.
Forssen does not teach that the mass ratio of botulinum toxin to protamine sulfate in the freeze-dried composition is between 1:5 and 1:20.
However, Forssen teaches that the pharmaceutical composition comprises about 10 Units to about 1000 Units botulinum toxin ([83]). Forssen teaches that the pharmaceutical composition is suitable for both human treatment or veterinary use and can be prepared by mixing and lyophilization ([113]).
Forssen also teaches that the concentration of the permeabilizing agent is 0.005 to 10 w/v% ([103]), Forssen teaches that the permeabilizing agent penetrates the patient’s bladder wall and preserves the biological activity of the substance obtained from clostridia ([7]).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to optimize by routine experimentation the amount of botulinum toxin in the composition as well as the amount of permeabilizing agent (protamine sulfate) in the pharmaceutical composition. Optimization of the amount of botulinum toxin based on the application (e.g. human or veterinary use) as well as the amount of permeabilizing agent for maximum permeability of the bladder wall would have resulted in a range of mass ratios between the botulinum toxin and the permeabilizing agent (protamine sulfate). The person of ordinary skill in the art would have had a reasonable expectation of success in a wide range of mass ratios between the botulinum toxin and the protamine sulfate.
Regarding claim 4, Forssen teaches that the pharmaceutical composition further comprises tonicity control agents such as mannitol ([115]).
Regarding claim 10, although Forssen teaches that botulinum toxin forms a complex with the permeabilizing agent, Forssen does not teach the pH of the pharmaceutical composition.
Gilsdorf teaches the isoelectric point of the native BONT/B light chain (LC) occurs at pH 6.3 (page 260, right column, Isoelectric focusing).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to control the pH above 6.3 such that the botulinum toxin is negatively charged in order to form a complex with the protamine sulfate. The person of ordinary skill in the art would have had a reasonable expectation of success in the addition of buffering agent to the composition to control the pH above 6.3. The range of above 6.3 overlaps with the claimed range of pH 6.0 to 7.0.
Forssen does not teach the amount of buffering agent within the pharmaceutical composition.
It would have been further obvious to the person of ordinary skill in the art to optimize by routine experimentation the amount of buffering agent within the composition in order to control the pH of the composition. The person of ordinary skill in the art would have had a reasonable expectation of success in controlling the pH of the composition based on the amount and type of buffering agent.
Regarding claim 11, Forssen teaches that the botulinum toxin is any of serotypes A, B, C, D, E, F, or G and the heavy or light chains thereof ([29]) and Gilsdorf teaches the isoelectric point of the native BONT/B light chain (LC) occurs at pH 6.3 (page 260, right column, Isoelectric focusing).
Regarding claim 12, Forssen teaches preparing a solution containing a permeabilizing agent and adding a solution to the substance obtained from clostridia to obtain a therapeutic composition ([127]).
Forssen also teaches that in some embodiments the permeabilizing agent forms a complex with botulinum toxin ([87]) and in some embodiments the permeabilizing agent is protamine sulfate ([89]). Forssen also teaches including a tonicity control agent (“isotonic agent”) such as mannitol and a buffering agent in the pharmaceutical composition ([115]). Forssen also teaches preparing the pharmaceutical composition as a lyophilisate ([113]).
Forssen does not explicitly teach the method steps of forming a complex, preparing a stock solution, and lyophilizing.
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to form the complex of botulinum toxin with protamine sulfate in the presence of a buffering agent, add mannitol (which is both an excipient and an isotonic agent), and lyophilize the mixture in order to prepare the pharmaceutical composition of Forssen for therapeutic use. The person of ordinary skill in the art would have had a reasonable expectation of success in forming a complex of botulinum toxin with protamine sulfate given the combined teachings of Park and Gilbert, which suggest that protamine sulfate forms a complex with other negatively charged molecules, such as botulinum toxin above its isoelectric point.
Forssen does not teach mixing botulinum toxin and protamine sulfate in a mass ratio of 1:5 to 1:20 botulinum toxin to protamine sulfate.
However, Forssen teaches that the pharmaceutical composition comprises about 10 Units to about 1000 Units botulinum toxin ([83]). Forssen teaches that the pharmaceutical composition is suitable for both human treatment or veterinary use and can be prepared by mixing and lyophilization ([113]).
Forssen also teaches that the concentration of the permeabilizing agent is 0.005 to 10 w/v% ([103]), Forssen teaches that the permeabilizing agent penetrates the patient’s bladder wall and preserves the biological activity of the substance obtained from clostridia ([7]).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to optimize the amount of botulinum toxin mixed with the amount of permeabilizing agent (protamine sulfate) in the pharmaceutical composition. Optimization of the amount of botulinum toxin based on the application (e.g. human or veterinary use) as well as the amount of permeabilizing agent for maximum permeability of the bladder wall would have resulted in a range of mass ratios between the botulinum toxin and the permeabilizing agent (protamine sulfate). The person of ordinary skill in the art would have had a reasonable expectation of success in a wide range of mass ratios between the botulinum toxin and the protamine sulfate.
Claim 2 is rejected under 35 U.S.C. 103 as being unpatentable over Forssen (RU 2720991 C2) in view of Park (International Anesthesiology Clinics 42.3 (2004): 135-145.) and Gilsdorf et al. (Protein Expression and Purification 46 (2006) 256–267), as applied to claims 1, 4, and 10-12 above, and as evidenced by Sigma (2025, website).
See discussion of Forssen, Park, and Gilsdorf above, which is incorporated into this rejection as well.
Regarding claim 2, Forssen teaches that the concentration of the permeabilizing agent is 0.005 to 10 w/v% ([103]), which is equivalent to 0.0098 mM to 20 mM (the molecular weight of protamine sulfate is 5.1 kDa as evidenced by Sigma, see molecular weight). The range of 0.0008 mM to 20 mM overlaps with the claimed range of 1.72 nM to 0.22 mM.
Claims 5-9 and 12 are rejected under 35 U.S.C. 103 as being unpatentable over Forssen (RU 2720991 C2) in view of Park (International Anesthesiology Clinics 42.3 (2004): 135-145.) and Gilsdorf et al. (Protein Expression and Purification 46 (2006) 256–267), as applied to claims 1, 4, and 10-12 above, further in view of Malanga et al. (Journal of pharmaceutical sciences 105.9 (2016): 2921-2931).
See discussion of Forssen, Park, and Gilsdorf above, which is incorporated into this rejection as well.
Regarding claim 5, Forssen teaches that the pharmaceutical composition further comprises tonicity agents such as mannitol ([115]).
Further regarding claim 5, Forssen teaches that both human serum albumin and protamine sulfate are permeability agents ([94] and [89])
However, Forssen does not teach that the composition comprises both human serum albumin and protamine sulfate.
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine human serum albumin and protamine sulfate in the composition because both human serum albumin and protamine sulfate are art-recognized equivalents for the same purpose (permeabilizing agents). See MPEP 2144.06 (I): “combining equivalents known for the same purpose.”
Further regarding claims 5 and 12, Forssen does not teach that the composition further comprises hydroxypropyl-beta-cyclodextrin.
Hydroxypropyl-beta-cyclodextrin is interpreted as encompassing both 2-hydroxypropyl-beta-cyclodextrin and 3-hydroxypropyl-beta-cyclodextrin.
Forssen teaches that in some embodiments of the invention, the composition further comprises a suitable polysaccharide as a stabilizer or adjuvant (([107]).
Malanga teaches that hydroxypropyl-beta-cyclodextrin (HPBCD) is a stabilizer for pharmaceutical formulations: Malanga teaches that HPBCD is the most versatile excipient among cyclic oligosaccharides that can be used in oral, rectal, dermal, ocular, and parenteral formulations and is used with a variety of active ingredients for its solubilizing and stabilizing effect (page 2921, Introduction, right column, paragraph 1).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to add hydroxypropyl-beta-cyclodextrin to the pharmaceutical composition of Forssen in order to stabilize the composition. The person of ordinary skill in the art would have been motivated by the teaching of Malanga, which suggests that hydroxypropyl-beta-cyclodextrin is beneficial for drug stability. The person of ordinary skill in the art would have had a reasonable expectation of success in the addition of hydroxypropyl-beta-cyclodextrin to the pharmaceutical composition of Forssen modified by Park and Gilsdorf.
Regarding claim 6, Forssen teaches adding an effective amount of a stabilizer to the pharmaceutical composition such that the amount is sufficient to positively affect release and/or activity of the botulinum toxin within the human body ([33]).
Malanga teaches that hydroxypropyl-beta-cyclodextrin is non-toxic in concentrations up to 200 mM (30.2 % w/v), which is above the claimed range (5 to 20 % w/v).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to routinely optimize the amount of hydroxypropyl-beta-cyclodextrin in Forssen’s pharmaceutical composition modified by Park and Gilsdorf in order to maximize the stability of the composition. The person of ordinary skill in the art would have had a reasonable expectation of success given that hydroxypropyl-beta-cyclodextrin is a highly versatile stabilizer in pharmaceutical drug formulations.
Regarding claim 7, Forssen teaches a concentration of the permeabilizing agent as 0.01 to 0.5 % w/v and exemplifies both human serum albumin and protamine sulfate as the permeabilizing agent ([94], [87], and Forssen claim 4). The range of 0.01 to 0.5 % w/v overlaps with the presently claimed range of 0.35 to 0.5 % w/v.
Regarding claims 8-9, although Forssen teaches that the pharmaceutical composition may comprise tonicity control agents such as mannitol ([115]), Forssen does not teach the concentration of mannitol in the composition.
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to routinely optimize the amount of the tonicity agent mannitol in the composition to control the tonicity of the composition and the person of ordinary skill in the art would have had a reasonable expectation of success in doing so.
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 CANDICE LEE SWIFT whose telephone number is (571)272-0177. The examiner can normally be reached M-F 8:00 AM-4:30 PM (Eastern).
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Louise Humphrey can be reached at (571)272-5543. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/LOUISE W HUMPHREY/Supervisory Patent Examiner, Art Unit 1657
/CANDICE LEE SWIFT/Examiner, Art Unit 1657
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