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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 11/11/2025 has been entered.
Amendments
Claim 4 has had a minor typographic change.
Claim Status
Claims 1-11 and 23-26 are currently pending.
Claim Interpretation
Claims 2-5 and 11 recite inherent properties and characteristics of BoNT/A6 or inherent to the administration of BoNT/A6. These recitations do not impart any limit on the structure of the composition used in the method of treatment nor do they impart limitations on the steps carried out within the claimed method. They are merely descriptive of the composition used in the method. Therefore, prior art which teaches or makes obvious the method of inducing local paralysis in a patient with BoNT/A6 will be considered for application under 35 U.S.C. 102 and/or 35 U.S.C. 103 regardless of whether the prior art reference also recognized the characteristics inherent to BoNT/A6.
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 (i.e., changing from AIA to pre-AIA ) 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.
Previous rejection under 35 U.S.C. § 103
RE: Rejection of claims 1-11 and 23-26 under 35 U.S.C. 103 as being unpatentable over Palan et al. (WO 2015/166242 A1; cited in IDS filed on 02/29/2024) in view of Pellett et al. (Toxicon, 2015, Vol. 107, pages 37-42; cited in IDS filed on 02/29/2024).
Applicant asserts that the pending claims are not obvious over Palan in view of Pellet because the properties of botulinum neurotoxin sub-serotype A6 (BoNT/A6) would not have been expected at the time of filing.
Specifically, the Pellett Declaration attests that BoNT subtypes are not interchangeable. Thus, it would have allegedly been unreasonable to assume that a particular BoNT is useful for a particular application in the absence of empirical data. Applicant asserts that at least two of the seven BoNT/A sub-serotypes are not therapeutically useful for administration to a patient and although the sequence of BoNT/A6 was known, there were no wet-lab studies describing the properties of BoNT/A6 at the time of filing and the sequence of BoNT alone is insufficient to predict the function of a BoNT in the absence of empirical evidence.
Applicant then discusses the differences between BoNT/A6 and BoNT/A1. Applicant summarizes that the discovery that BoNT/A6 has improved cell entry kinetics is unexpected given 1) the overall sequence similarity between BoNT/A1 and BoNT/A6, 2) the lack of empirical data describing the function of BoNT/A6, and 3) the numerous amino acid substitutions in the heavy chain of BoNT/A6 relative to BoNT/A2.
Applicant’s arguments have been fully considered but are not sufficient to overcome the rejection of record.
As discussed throughout prosecution, it is appreciated that the characteristics of BoNT/A6 are different from BoNT/A1 (and the other BoNT/A sub-serotypes) and the cell-entry kinetics were not known as of the effective filing date. However, that does not necessarily mean that its use is non-obvious.
Palan describes (1) the existence of BoNT/A6 (p. 1, lines 9-21 and p. 7, lines 32-34) and (2) teaches methods of inducing paralysis through administration of BoNT/A6 (p. 9, lines 16-18 and 26-30; p. 10, lines 30-31). Because Palan teaches the existence of BoNT/A6 and its usefulness in inducing paralysis, it would have been obvious to have used such a composition for the purpose of inducing local paralysis in a patient, especially when read in view of Pellett, which demonstrates that BoNT/A1-A5 were each capable of causing local paralysis with varying times of onset (p. 39, left col., par. 2; p. 41, fig. 3).
And although it is acknowledged that Pellett discusses the reduced activity of BoNT/A3-A4 (p. 2, par. 3), that does not mean that other uncharacterized sub-serotypes would be expected to be clinically irrelevant. Pellett teaches that although most of the focus is on BoNT/A1 and B1, the other BoNT variants are “a potential treasure trove for discovery of new information on these toxins” and “further in depth functional studies of these and additional BoNT variants will increase our molecular understanding of these toxins” (p. 7, par. 1). Moreover, it was previously known that some sub-serotypes could have superior cell-entry kinetics when compared to BoNT/A1. For example, Pellett states “BoNT/A2 enters neuronal cells faster” (p. 5, par. 3).
In summary, Palan clearly discloses the use of BoNT/A6 for inducing paralysis and even if Palan was required to appreciate every characteristic of BoNT/A6 (a point which the examiner does not concede), Pellett provides substantial motivation to test other BoNT subtypes as they may be superior to BoNT/A1. And although the superiority of a property shared with the prior art is evidence of nonobviousness (MPEP § 716.02(a)(II)), merely finding that BoNT/A6 has superior cell-entry kinetics when compared to another BoNT is not sufficient to outweigh the explicit teachings by Palan that BoNT/A6 can be used for exactly this purpose.
For at least these reasons, the examiner reasserts that the claims do not overcome the teachings of Palan in view of Pellett. The rejection of record has been maintained.
Maintained rejections under 35 U.S.C. § 103
Claims 1-11 and 23-26 are rejected under 35 U.S.C. 103 as being unpatentable over Palan et al. (WO 2015/166242 A1; cited in IDS filed on 02/29/2024) in view of Pellett et al. (Toxicon, 2015, Vol. 107, pages 37-42; cited in IDS filed on 02/29/2024).
Palan et al. (hereinafter Palan) describes methods for producing recombinant Clostridium botulinum neurotoxins of serotype A (BoNT/A)(p. 1, lines 5-6). Palan teaches that there are at least seven different classes of botulinum neurotoxin (A, B, C1, D, E, F, and G) and these are the most potent toxins known, with a median lethal dose (LD50) of 0.5 to 5 ng/kg depending on the serotype (p. 1, lines 9-21). Among the serotypes, the BoNT proteins are further divided into different subtypes on the basis of amino acid percentage sequence identity (p. 1, lines 17-18). The BoNT/A serotype is divided into at least eight subtypes (BoNT/A1 through BoNT/A8), which share at least 84% amino acid sequence identity with each other (p. 7, lines 32-34). Palan discloses the purification and full-length amino acid sequence of BoNT/A6 (p. 10, lines 30-31; p. 56, line 29 through p. 30, line 10). Palan teaches that clostridial neurotoxins are synthesized as single-chain polypeptides that are modified post-translationally by a proteolytic cleavage event to form two polypeptide chains joined together by a disulfide bond (i.e., a di-chain BoNT/A protein)(p. 1, lines 29-31). Although the invention of Palan is primarily directed towards methods of manufacturing BoNT using Escherichia coli and Lys-C (a commercially available endoproteinase)(p. 2, line 30 through p. 3, line 3; p. 3, line 32 through p. 4, line 2), Palan also teaches a method of treatment comprising administration of an active di-chain BoNT/A protein, composition, or liquid pharmaceutical composition of the invention to a patient in need thereof (p. 7, lines 16-18).
Regarding claim 1, Palan teaches a method of treatment comprising administration of an active di-chain BoNT/A protein, composition, or liquid pharmaceutical composition of the invention to a patient in need thereof (p. 7, lines 16-18; claims 18 and 20).
With respect to the method of inducing local paralysis with BoNT/A6, Palan teaches administration of BoNT/A and further teaches that the BoNT/A may be a single-chain or di-chain protein comprising the sequence of BoNT/A6 (p. 9, lines 16-18 and 26-30 and p. 10, lines 30-31). Palan’s disclosure is directed to the administration of only one BoNT/A subtype (e.g., a composition consisting of BoNT/A6), rather than a combination of multiple subtypes (e.g., a composition comprising BoNT/A6) because Palan discloses that the method is used to produce the di-chain of any BoNT/A subtype (p. 9, lines 20-22) resulting from the culture of a single BoNT/A transformed cell (p. 48, lines 20-25). Palan further teaches that BoNTs are “well known for their ability to cause flaccid muscle paralysis” and “said muscle-relaxant properties have led to botulinum neurotoxins (such as BoNT/A) being employed in a variety of medical and cosmetic procedures” including a list encompassing local muscle paralysis (p. 2, lines 23-28). Palan does not use to exact words “including local paralysis”.
Nevertheless, Pellett teaches that BoNT/A is the most commonly used BoNT serotype for medical purposes (p. 37, right col., par. 2). Pellett further teaches that BoNT subtypes can be used to induce local paralysis (abstract). For example, Pellett investigated the administration of BoNT subtypes A1-A5 by intramuscular injection in mice (Fig. 5) and demonstrates that each of the BoNT subtypes were capable of causing local paralysis with some subtypes, such as BoNT/A2, having significantly more rapid increase in local paralysis when compared to other BoNT/A subtypes (p. 39, left col., par. 2; p. 41, fig. 3). Pellett teaches that ten subtypes have been identified for BoNT/A and analysis of several of these subtypes have revealed distinct characteristics, ranging from differences in cell entry and enzyme kinetics to differences in potent in mice and cell-model specific potency (abstract). BoNT/A2 has been studied in vitro and more potently causes local paralysis compared to BoNT/A1 likely due to its improved cell entry kinetics (p. 38, left col., par. 2).
Accordingly, because Palan teaches methods for treating patients with BoNT/A toxins including BoNT/A6 and because Pellett teaches that BoNT/A toxins can be administered to induce local paralysis, it would have been obvious to have modified the method of Palan such that is it is a method of inducing local paralysis with BoNT/A6. There would have been a reasonable expectation of success because both Palan and Pellett demonstrate that BoNT/A subtypes are universally useful in inducing local paralysis but differ in their characteristics such as cell entry and enzyme kinetics as well as potency. There is no evidence that the properties of BoNT/A6 are remarkable or unexpected because Pellett demonstrates the existence of BoNT/A toxins, such as BoNT/A2, which have superior cell entry kinetics when compared to BoNT/A1. Although applicant’s disclosure was not relied upon in arriving at this determination of obviousness, it is noted that applicant describes their BoNT/A6 findings as being “similar to BoNT/A2” (specification, [0090]), thus the disclosure does not clearly establish unexpected properties when compared to the BoNT/A subtype as a whole. This obviousness is based upon the “Some Teaching, Suggestion, or Motivation in the Prior Art That Would Have Led One of Ordinary Skill To Modify the Prior Art Reference or To Combine Prior Art Reference Teachings To Arrive at the Claimed Invention” rationale set forth in KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395-97 (2007). See MPEP 2143(I)(G).
Accordingly, Palan in view of Pellett makes obvious a method of inducing local paralysis in a patient comprising administering to the patient an effective amount of a preparation comprising Clostridium botulinum neurotoxin, wherein the neurotoxin is BoNT/A6.
With respect to intramuscular administration, Palan teaches that the composition is to be applied intramuscularly (p. 43, lines 5-7; p. 45, lines 26-30). And although Palan does not use the word “injection”, intra-muscular administration is readily understood to be synonymous with intramuscular injection. Similarly, Pellett teaches IM injection of BoNT/A subtypes to induce local paralysis (p. 38, right col., par. 3).
With respect to the amount of the composition, although Palan does not explicitly teach administration of “an effective amount”, Palan teaches that a therapeutically effective dose is the amount of neurotoxin which prevents, ameliorates or treats the symptoms accompanying the disease and the dosage regiment will be determined by the attending physician and other clinical factors (p. 43, lines 19-30). In addition, Palan teaches that the compositions are administered at least once in order to treat or ameliorate or prevent a disease or condition (p. 43, line 34 through p. 44, line 2). Accordingly, Palan teaches administration of the composition in an effective amount because this amount necessarily must be one which prevents, ameliorates, or treats the symptoms of the accompanying disease (such as by performing the well-understood function of including local paralysis).
With respect to the effective amount being less than the amount of BoNT/A1 to induce local paralysis, Palan does not compare the dosing of BoNT/A6 to BoNT/A1 with respect to the amount required to induce local paralysis. Nevertheless, as discussed above, a person having ordinary skill in the art would have been prompted to determine the “effective amount” through routine optimization based upon (i) Palan’s disclosure that BoNT LD50 values range from 0.5 to 5 ng/kg and that BoNT neurotoxins have differing efficacy (p. 1, lines 20-27) and (ii) Pellet’s disclosure that it is understood that BoNT subtypes have distinct characteristics such as cell entry and enzyme kinetics. Therefore, in routinely determining the LD50 values of BoNT serotypes, a person having ordinary skill in the art would have arrived at an effective amount of serotype A6 which is lower than needed when using subtype A1 with a reasonable expectation of success due to its inherently higher potency. There would have also existed a reasonable expectation of success because Palan teaches that the determination of efficacy is a standard pharmaceutical procedure, and the dosage regiment will be determined by the attending physician and other clinical factors (p. 43, lines 19-30).
Thus, claim 1 is made obvious by the teachings of Palan in view of Pellett as a result of routine experimentation.
Regarding claims 2-5 and 11, the instant claims are drawn to inherent properties of BoNT/A6. "[T]he discovery of a previously unappreciated property of a prior art composition, or of a scientific explanation for the prior art’s functioning, does not render the old composition patentably new to the discoverer." Atlas Powder Co. v. IRECO Inc., 190 F.3d 1342, 1347, 51 USPQ2d 1943, 1947 (Fed. Cir. 1999). Therefore, claims 2-5 and 11 are anticipated regardless of whether Palan or any other prior art disclosure recognized the enzymatic characteristics possessed by BoNT/A6 or its inherent differences when compared to BoNT/A1. See MPEP § 2112(I) and (II).
Regarding claims 6-7, as discussed above, Palan in view of Pellett makes obvious a method of inducing local paralysis. Palan further teaches that the medicament can be used for prevention and/or treatment of cervical dystonia, blepharospasm, hyperhidrosis, strabismus, achalasia, and migraine (i.e., nervous system or neuromuscular conditions)(p. 2, lines 23-29; p. 44, line 8 through p. 45, line 24).
Regarding claim 8, Palan teaches that the active di-chain BoNT/A proteins can be used in therapy and suitable therapies may include cosmetic treatments (p. 44, lines 5-7).
Regarding claims 9-10, Palan does not explicitly teach that the preparation comprises at least 95% pure A6 toxin or toxin complex but the purification of the composition is nonetheless obvious through routine optimization. A person having ordinary skill in the art would have arrived at the recited levels of purity (95% and 98%) as a result of routine optimization and would have been prompted to do so by Palan’s teaching that it may be useful to purify the BoNT/A single- and di-chain proteins (p. 18, lines 16-18 and 20-23; p. 24, lines 19-28; p. 28, lines 9-20) to remove contaminants such as protamine sulfate, remaining DNA, parts of smaller proteins, and middle sized proteins as well as the hemagglutinins of the botulinum neurotoxin protein complex (p. 28, lines 9-20). A person having ordinary skill in the art would have had a reasonable expectation of success because simply increasing the purity of the active compound (BoNT/A6) would result in a composition which would be reasonably expected to more efficiently induce local paralysis in a patient. See MPEP 2144.05(II)(A).
Regarding claim 23, Palan teaches that BoNT/A can be used for the treatment of cervical dystonia, blepharospasm, strabismus, achalasia, migraine, cosmetic issues, spasms, hemifacial spasm, torticollis, cerebral palsy, spasmodic dysphonia, multiple sclerosis, Parkinson’s disease, masticatory spasms, anal fissures, bladder dysfunction, bruxism, myokymia, and wrinkles (p. 2, lines 23-28; p. 44, line 8 through p. 45, line 24).
Regarding claim 24, Palan does not disclose a preparation comprising 100 units of Clostridium botulinum neurotoxin BoNT/A6. Nevertheless, a person having ordinary skill in the art could have arrived at this amount as a result of routine optimization. A person having ordinary skill in the art would have been prompted to experiment to determine an appropriate amount to administer to a subject in need thereof based upon Palan’s teaching that a therapeutically effective dose is the amount of neurotoxin which prevents, ameliorates or treats the symptoms accompanying the disease and the dosage regiment will be determined by the attending physician and other clinical factors (p. 43, lines 19-30). Palan describes the methodology for determining an effective amount as being “well known in the medical arts” and teaches that dosages for any one patient depend upon many factors, including the patient’s size, body surface area, age, the particular compound to be administered (e.g., that the amount depends on the pharmacodynamic properties of the BoNT), time of administration, route of administration, general health, and other drugs being administered concurrently (p. 43, lines 29-33). There would have been a reasonable expectation of success because Palan teaches that the therapeutic efficacy and toxicity of the compound can be determined by standard pharmaceutical procedures in cell cultures or experimental animals (p. 43, lines 22-25). Applicant’s disclosure has been fully reviewed and there is no evidence that the recited amount is critical and/or elicits a remarkable or unexpected result. Thus, a person having ordinary skill in the art could have arrived at a dose of 100 units of Clostridium botulinum neurotoxin BoNT/A6 as a result of routine optimization (MPEP § 2144.05(II)(A)).
Regarding claim 25, although Palan does not explicitly state that the preparation is at least 90% pure, a person having ordinary skill in the art would have arrived at the recited level of purity as a result of routine optimization and would have been prompted to do so by Palan’s teaching that it may be useful to purify the BoNT/A single- and di-chain proteins to remove contaminants such as protamine sulfate, remaining DNA, parts of smaller proteins, and middle sized proteins as well as the hemagglutinins of the botulinum neurotoxin protein complex (p. 18, lines 16-18 and 20-23; p. 24, lines 19-28; p. 28, lines 9-20). A person having ordinary skill in the art would have had a reasonable expectation of success because simply increasing the purity of the active compound (BoNT/A6) would be reasonably expected to result in a composition which would more efficiently induce local paralysis in a patient. See MPEP § 2144.05(II)(A).
Regarding claim 26, applicant has not provided a special definition for “single dose form”. This term has therefore been interpreted in its broadest reasonable form to encompass any administration form of administration which takes place over a single timepoint (i.e., a non-continuous administration such as an infusion). Palan discusses various administration methods including conventional intramuscular administration (p. 43, lines 5-7). Palan further teaches that the pharmaceutical compositions and formulations “are administered at least once in order to treat or ameliorate or prevent a disease or condition recited in this specification” (p. 43, line 34 through p. 44, line 2). Additionally, Palan teaches that the composition can be in liquid form and sealed in a vial or in a ready-to-use device such as a syringe (p. 41, lines 21-23) and teaches that dosage regimens can be determined by physicians and other clinical factors (p. 43, lines 29-33). Finally, Palan describes a process of reconstituting (with saline or water) a lyophilized material to create a solution or composition containing the BoNT/A protein “to be administered to a patient” (p. 42, lines 2-4). Therefore, Palan implicitly teaches or at least makes obvious administration in a single dose form.
Conclusion
No claim is allowed.
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/GRANT C CURRENS/Examiner, Art Unit 1651