DETAILED ACTION
Status of claim rejections
The objection to the specification is withdrawn in view of Applicant’s arguments in the response filed 01/09/2026.
The objections to the drawings are withdrawn in view of Applicant’s arguments in the response filed 01/09/2026.
The rejection of the claims under 35 USC 112(b) is withdrawn in view of Applicant’s amendments/cancellation of the claims in the response filed 01/09/2026.
The rejection of the claims under 35 USC 112(a) enablement is maintained and modified in view of Applicant’s amendments/arguments in the response filed 01/09/2026.
The rejection of the claims under 35 USC 112(a) written description is maintained and modified in view of Applicant’s amendments/arguments in the response filed 01/09/2026.
This Action is FINAL, as necessitated by Applicant’s amendments.
New Objections - Specification
The disclosure is objected to because of the following informalities: the specification refers to the drawings as “Figure” instead of “FIG.”
Appropriate correction is required.
New Claim Objections
Claim 1 objected to because of the following informalities: claim 1 recites, inter alia, “a mutation at Glu148 of of a wild-type botulinum toxin light chain”. The second “of” should be deleted to make the phrase grammatically correct. Claim 1 also recites “binding ot the protease to a neuronal SNARE protein that acts as a substrate for the wild-type botulinum toxin light chain”. The examiner suggests rewriting the phrase to recite “binding of the protease to a neuronal SNARE protein that acts as a substrate for the wild-type botulinum toxin light chain”.
New Claim Rejections - 35 USC § 112(b)
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.
Claims 1-5, 7, 10 and 18-19 are 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 1 recites “a method of treating an individual having a disease process mediated by a non-neuronal SNARE protein, comprising: providing a pharmaceutical comprising a synthetic peptide having a protease activity characterized by substrate specificity for the non-neuronal SNARE protein having an exosite, wherein the protease comprises a botulinum neurotoxin serotvpe A light chain comprising an exosite recognition sequence. wherein the exosite recognition sequence comprises a mutation at Glu148 of a wild-type botulinum toxin light chain, wherein the mutation comprises insertion of a non- native exosite recognition sequence interacts with the exosite of the non- neuronal SNARE protein, and wherein the mutation is selected to provide improved binding between the protease and the non-neuronal SNARE protein relative to binding of the protease to a neuronal SNARE protein that acts as a substrate for the wild-type botulinum toxin light chain; and administering the pharmaceutical to the individual on a schedule effective to reduce the secretory activity” (emphasis added).
It is noted that the claim has a period between the word “sequence” and the second “wherein” clause. A claim must be a complete sentence that begins with a capital letter and ends with a period. Because there is a period in the middle of the claim, this renders the claim indefinite because it is unclear whether the claim ends after the period. For the purposes of compact patent prosecution, the examiner is interpreting the claim to continue after the period (i.e, that the period is a comma). Please note that the dependent claims are also indefinite due to dependency on claim 1.
Claim 1 recites the limitation “wherein the exosite recognition sequence comprises a mutation at Glu148 of of a wild-type botulinum toxin light chain, wherein the mutation comprises insertion of a non-native exosite recognition sequence interacts with the exosite of the non-neuronal SNARE protein, and wherein the mutation is selected to provide improved binding between the protease and the non-neuronal SNARE protein relative to binding ot the protease to a neuronal SNARE protein that acts as a substrate for the wild-type botulinum toxin light chain.” The claim seems to recite two different mutations (mutation of Glu148 in a wild type botulinum toxin light chain and an insertion of a non-native exosite recognition sequence). However, it is unclear which mutation would “provide improved binding between the protease and the non-neuronal SNARE protein relative to binding of the protease to a neuronal SNARE protein” as instantly claimed or if both mutations are conferring the improved binding. Thus, the claim is indefinite. For the purposes of compact patent prosecution, the examiner is interpreting the insertion of the non-native exosite recognition sequence to confer the improved binding. Please note that the dependent claims are also indefinite due to dependency on claim 1.
Claim 1 recites the limitation "to reduce the secretory activity". There is insufficient antecedent basis for this limitation in the claim. As amended, claim 1 does not recite any secretory activity earlier in the claim. As such, the claim is indefinite. Please note that the dependent claims are also indefinite due to dependency on claim 1.
Claim 7 recites, inter alia, "one or more mutations to sites corresponding a mutation of Glu148 of SEQ ID NO: 4". It is unclear if the claim requires multiple mutations at the same position (i.e., Glu148 [Wingdings font/0xE0] Ser148 [Wingdings font/0xE0] Pro148) or if the claim requires other mutations within the non-native exosite recognition sequence other than Glu148, or just the Glu148 mutation. Thus, the claim is indefinite. For the purposes of compact patent prosecution, the examiner is interpreting the claim to require just the Glu148 mutation (as recited in claim 1).
Claim 10 recites, inter alia, “The protease of claim 7, wherein the mutation of Glu148 is selected from the group consisting of Met and Val.” The claim is indefinite because the claim 7 is drawn to a method, not a protease.
Claim 19 recites that “the non-neuronal SNARE protein is administered as a formulation selected from the group consisting of an injectable liquid, a topical preparation, a suspension, an ointment, a gel, a lotion, a cream, .a patch configured for topical application, a film configured for topical application, a powder configured for inhalation, a vapor, a droplet mist, a sublingual drop, a lozenge, a nasal spray, an eye drop, a suppository, and a pessary.” However, the method of claim 1 requires administration of a synthetic peptide having substrate specificity for the non-neuronal SNARE protein (e.g., targeting the non-neuronal SNARE protein with a mutated botulinum neurotoxin serotype A light chain to treat the disease state). Thus, it is unclear how the non-neuronal SNARE protein itself would be administered for the treatment of the disease(s) encompassed by the claims when the claim requires targeting the non-neuronal SNARE protein and the claim is indefinite. For the purposes of compact patent prosecution, the examiner is interpreting the pharmaceutical composition recited in claim 1 to be administered in the claimed Markush group of formulations.
Claim 19, as recited above, also contains a period in the line reciting “a cream, .a patch configured for topical application” (emphasis added). A claim must be a complete sentence that begins with a capital letter and ends with a period. Because there is a period in the middle of the claim, this renders the claim indefinite because it is unclear whether the claim ends after the period. For the purposes of compact patent prosecution, the examiner is interpreting the claim to continue after the period (i.e, that the period is a comma).
Claim Interpretation
Claim 1, recites, inter alia, “administering the pharmaceutical to the individual on a schedule effective to reduce the secretory activity.” The examiner has interpreted the limitation under broadest reasonable interpretation to encompass any administration schedule capable of reducing secretory activity in an individual with a disease process associated with non-neuronal SNARE proteins (e.g., administration of an effective amount of the composition; see Non-Final Office Action).
Modified Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
First rejection
Claims 1-5, 7, 10 and 18-19 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
While determining whether a specification is enabling, one considered whether the claimed invention provides sufficient guidance to make and use the claimed invention, if not, whether an artisan would have required undue experimentation to make and use the claimed invention and whether working examples have been provided. There are many factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is “undue.” These factors include, but are not limited to:
(A) The breadth of the claims;
(B) The nature of the invention;
(C) The state of the prior art;
(D) The level of one of ordinary skill;
(E) The level of predictability in the art;
(F) The amount of direction provided by the inventor;
(G) The existence of working examples; and
(H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988).
All Wands factors listed above have been considered with regard to the instant claims, with the relevant factors discussed below.
Furthermore, the USPTO does not have laboratory facilities to test if an invention with function as claimed when working examples are not disclosed in the specification, therefore, enablement issues are raised and discussed based on the state of knowledge pertinent to an art at the time of the invention, therefore, skepticism raised in the enablement rejection are those raised in the art by artisans of expertise.
Nature of the invention: Claims 1-5, 7, 10 and 18-19 are drawn to “a method of treating an individual having a disease process mediated by a non-neuronal SNARE protein, comprising: providing a pharmaceutical comprising a synthetic peptide having a protease activity characterized by substrate specificity for the non-neuronal SNARE protein having an exosite, wherein the protease comprises a botulinum neurotoxin serotvpe A light chain comprising an exosite recognition sequence. wherein the exosite recognition sequence comprises a mutation at Glu148 of a wild-type botulinum toxin light chain, wherein the mutation comprises insertion of a non- native exosite recognition sequence interacts with the exosite of the non-neuronal SNARE protein, and wherein the mutation is selected to provide improved binding between the protease and the non-neuronal SNARE protein relative to binding of the protease to a neuronal SNARE protein that acts as a substrate for the wild-type botulinum toxin light chain; and administering the pharmaceutical to the individual on a schedule effective to reduce the secretory activity.” Claim 2 requires the “the synthetic peptide comprises a targeting moiety.” Claim 3 requires the “the targeting moiety binds to cells or tissues associated with the secretory activity”. Claim 4 requires that the targeting moiety supports binding of the synthetic peptide to a cell and transportation to the cell interior. Claim 5 requires the targeting moiety is selected from the group consisting of an antibody, and antibody fragment, a receptor ligand, a pharmaceutical compound, a microparticle, and an aptamer. Claim 7 requires the non-native exosite recognition sequence comprises one or more mutations to sites corresponding to one or more of the group consisting of Glu148 of SEQ ID NO: 4. Claim 10 requires that the mutation of Glul48 is selected from the group consisting of Met and Val. Moreover, claim 18 requires the non-neuronal SNARE protein is selected from the group consisting of SNAP-23 and claim 19 requires the formulation to be an injectable liquid, a topical preparation, a suspension, an ointment, a gel, a lotion, a cream, a patch configured for topical application, a film configured for topical application, a powder configured for inhalation, a vapor, a droplet mist, a sublingual drop, a lozenge, a nasal spray, an eye drop, a suppository, and a pessary.
The breadth of the claims: The “method of treating an individual having a disease process mediated by a non-neuronal SNARE protein” has been interpreted under broadest reasonable interpretation to include the treatment of any non-neuronal SNARE protein mediated diseases (e.g., hypersecretory disorders like abhorrent secretion of airway mucus, antibodies, insulin, gastric acids, and ions including gastric hypersecretion, hyperhidrosis, asthma, COPD, cystic fibrosis, hyperthyroidism, hyperpituitarism, hypercortisolism, type 2 diabetes/insulin hypersecretion, etc.) by administering any synthetic peptide having a mutant botulinum A toxin light chain protease as a pharmaceutical containing a mutation at Glu148. This claim limitation also encompasses the pharmaceutical being capable of producing a de minimis ability to provide improved binding between the protease and a non-neuronal SNARE protein, as well as reduced secretory activity by administering the pharmaceutical at essentially any time.
The claims also encompass the use of any administration route to achieve the treatment. Administration routes include direct injection (subcutaneous, intravenous, intramuscular, intrathecal, intracorporeal, intraperitoneal, etc.), topical administration, droplets, oral administration, suspensions, transdermal patches, powder, vapors, mists, nasal sprays, suppositories, consumable foods/liquids, etc.
The level of skill in the art: The level of skill is high, including, e.g., a researcher with a PhD degree.
The working examples and guidance provided: The specification fails to provide any working examples in which any pharmaceutical composition having the claimed synthetic protease with a mutation of a wild-type botulinum toxin A light chain (where the mutation provides improved binding between the protease and the non-neuronal SNARE protein relative to a neuronal SNARE protein) is administered via any administration route to subjects having any and all disease processes mediated by non-neuronal SNARE proteins, where the pharmaceutical is given to the individual on a schedule effective to reduce the secretory activity.
The state and unpredictable nature of the prior art: The state of the prior art for treating any and all diseases characterized by elevated secretory activity by administering the claimed synthetic peptide with a mutation of a wild-type botulinum neurotoxin serotype A light chain (where the mutation provides improved binding between the protease and the non-neuronal SNARE protein relative to a neuronal SNARE protein) was unpredictable before the effective filing date of the claimed invention.
Treatments of individuals having different hypersecretory disorders (i.e., non-neuronal SNARE protein disease states as encompassed by the claims):
Flume et al. (State of progress in treating cystic fibrosis respiratory disease. BMC Med 10, 88 (2012)) teaches various treatment modalities for cystic fibrosis including CFTR gene modulation, direct instillation of salt and water in the CF airway epithelia, inhaled mannitol, and airway clearance therapies (see pg. 6-7). Flume teaches use of medications that could be used to alter properties of airway phlegm, aerosolized antibiotics, anti-inflammatory medications, and lung transplantation (see pg.6-7). Flume further teaches these therapies do not offer a cure and they mainly treat downstream complications of the pathophysiology of CF lung disease, meaning that patients continue to suffer the morbidity associated with chronic airways infection and predicted survival still lags well below what is normal (see pg. 8). Here, the art recognizes various treatment modalities for cystic fibrosis, however, even when treating the downstream complications of the disease pathophysiology, patients still carry high morbidity. The art is also silent to the treatment of this hypersecretory disorder via the use of synthetic botulinum neurotoxin peptides.
Mayo Clinic (Numerous Treatment options for Hyperthyroidism. May 6, 2012. Retrieved 09/19/2025 from https://newsnetwork.mayoclinic.org/discussion/numerous-treatment-options-for-hyperthyroidism/) teaches that “[i]n addition to surgery. . . there are three treatment options for hyperthyroidism. The first is surgery to remove the entire thyroid (thyroidectomy). Thyroidectomy is effective and carries a low risk of complications when performed by an experienced surgeon. However, it leaves a person with an underactive thyroid once the gland has been removed. . .and [they] would need to take thyroid hormone in the form of a pill, once daily for the rest of [their] life to regulate [the] body’s metabolism. . .The second option is radioactive iodine therapy. A radioactive form of iodine is givenby mouth and becomes concentrated in the thyroid. The radiation destroys the thyroid gland tissue over several weeks. . . The third option is to take an oral anti-thyroid medication, typically propylthiouracil ormethimazole (Tapazole), which prevents the thyroid from producing too muchhormone. Symptoms usually begin to improve in six to 12 weeks, but medicationtherapy typically continues for at least a year or more” (see pg. 2-3). Here, the art only recognizes 3 different treatment modalities for hyperthyroidism, and is also silent to the treatment of this hypersecretory disorder via the use of synthetic botulinum neurotoxins.
As evidenced by the prior art cited above, different hypersecretory disorders (i.e., non-neuronal SNARE protein mediated diseases as contemplated by the broad instant claims) has no common mechanism of action, symptoms, or treatment. None of the treatments used or contemplated by the prior art between the different disease states overlap. Further, there is no single, end-all-be-all treatment capable of treating the broad genus of any and all hypersecretory disorders encompassed by the instant claims. The art available at the time of filing fails to exemplify the efficacy of a single product against all hypersecretory disorders generally.
Art-recognized uses and administration of botulinum A toxins: Allergan (“FDA Guidance for Industry: Scientific Considerations in Demonstrating Biosimilarity to a Reference Product”; available online April 16, 2012; retrieved 09/18/2025 from https://downloads.regulations.gov/FDA-2011-D-0605-0043/attachment_1.pdf) teaches “specific C. botulinum toxins have been developed as therapeutic biologics for human use. These include botulinum toxin serotype A biologics, which have been approved for use in many countries, and additional serotype A biologics, which are in various stages of clinical development. The biologics approved for commercial use have been used to treat various disorders, including strabismus (misalignment of the eyes), blepharospasm (uncontrollable, forcible closure of the eyelids caused by a progressive dysfunction of the nerve that controls muscles around the eye), cervical dystonia (uncontrollable tightening and twisting of the neck), upper limb spasticity (e.g., increase in muscle tone following stroke, traumatic brain injury, spinal cord injury or demyelinating disorder making it difficult to move the limb normally), chronic migraine (headache at least 15 days per month with headaches lasting 4 hours or more per day), urinary incontinence due to detrusor overactivity associated with a neurologic condition (e.g., spinal cord injury, multiple sclerosis), severe primary axillary hyperhidrosis (extremely excessive underarm sweating), and moderate to severe glabellar lines (cosmetic indication)” (see pg. 1-2). On pg. 2, the reference only indicates botulinum toxin as an injectable medication. Here, the prior art at the time of filing demonstrates the recognized uses of botulinum toxin serotype A for treatments of various disorders, including axillary hyperhidrosis. However, the prior art does not contemplate that any and all botulinum toxin serotypes (mutated or otherwise) were capable or known to be used for treating any and all hypersecretory disorders as contemplated by the instant claims.
Ramirez-Castaneda (Diffusion, spread, and migration of botulinum toxin. Mov Disord. 2013 Nov;28(13):1775-83) teaches that “in addition to a detailed knowledge of the disorder being treated, the appropriate and optimal use of BoNT requires a comprehensive knowledge of its mechanisms of action, biologic properties, distribution characteristics, therapeutic action, adverse effect profile, and the anatomy of the area targeted for injection. Understanding the various factors that influence the local and systemic distribution of BoNT is essential for the development of better BoNT products. The local and systemic distribution of BoNT depends on the following factors: (1) spread refers to a physical
movement of the toxin from one site to another and it is dependent on a number of variables related to the injection technique, volume, needle size, and other physical factors; (2) diffusion refers to a more microscopic phenomenon in which a soluble molecule is dispersed by a passive transport beyond its original injection site; (3) migration refers to the spread to distant sites that can occur either via the nerves (neuroaxonal transport) or by blood (hematogenous transport); and (4) volume and dilution” (see pg. 1775; see Fig. 1; see Table 1). Here, the reference clearly contemplates only injection (e.g., intramuscular) as a means of administering botulinum toxin for the treatment of diseases. Even so, the reference also clearly recognizes that even using only injection as the means of administration, comprehensive knowledge of its mechanisms of action, biologic properties, distribution characteristics, therapeutic action, adverse effect profile, and the anatomy of the area targeted are crucial for the use of the toxin as a treatment modality. The art does not contemplate any other administration routes (inhalation, droplets, oral administration, suspensions, transdermal patches, powder, vapors, mists, nasal sprays, suppositories, consumable foods/liquids, etc.) as encompassed by the scope of the instant claims.
Chen (2012; Clinical Uses of Botulinum Neurotoxins: Current Indications, Limitations and Future Developments. Toxins, 4(10), 913-939; cited in IDS filed 05/09/2022) teaches that “botulinum neurotoxins (BoNTs) are organized into three functional domains: an N-terminal catalytic domain (light chain, LC), an internal translocation domain (heavy chain, HCT), and a C-terminal receptor binding domain (heavy chain, HCR). There are seven serotypes of BoNTs termed A–G. Each serotype of BoNT cleaves one of the SNARE proteins, VAMP2, SNAP25, or syntaxin 1a” (see pg. 913-914). Chen also specifically embodies a K224D mutated botulinum neurotoxin E light chain capable of cleaving SNAP23 and the natural substrate, SNAP25, but not SNAP29 or SNAP47. Upon direct protein delivery into cultured human epithelial cells, LC/E(K224D) cleaved endogenous SNAP23 so as to inhibit the secretion of mucin and IL-8 (i.e., the mutant has structure to perform Applicant’s claimed function) (see pg. 925, paragraph 1, and Fig. 4). While the art recognizes this specific botulinum E serotype light chain mutant for the claimed function of non-neuronal SNARE targeting, the art fails to recognize the efficacy of mutation of botulinum serotype A mutated at Glu148 (i.e., to any other amino acid as encompassed by the claims) for the treatment of all on-neuronal SNARE protein mediated diseases.
The extremely broad scope of the claims and lack of guidance in the specification exacerbates a highly unpredictable art. While the results presented in the art do not necessarily preclude Applicant’s hypotheses regarding treating an individual having diseases characterized by an elevated secretory activity using modified/mutated botulinum A neurotoxins to target non-neuronal cells, they certainly fail to support it in its totality that the claimed pharmaceutical is capable of the functions as instantly claimed. Applicants do not provide the details of how one of ordinary skill would reasonably administer the compositions as instantly claimed to a subject and assess the effect of the administered compound on being capable of producing at least some de minimis ability to provide improved binding between the protease and a non-neuronal SNARE protein, as well as reduced secretory activity by administering the pharmaceutical at essentially any time, nor is there a reduction to practice of the instant method.
Consequently, the state of the art, when combined with the lack of any disclosed direct experimental test of Applicant’s hypothesis, shows that one of ordinary skill would have no basis to reasonably predict or conclude that administration of a composition possessing a synthetic peptide having substrate specificity to a non-neuronal SNARE protein, and a mutation in a non-native exosite recognition sequence would result in tangible effects (provide improved binding between the protease and the non-neuronal SNARE protein and result in reducing the secretory activity) as instantly claimed. Though not controlling, the lack of working examples is, nevertheless, a factor to be considered in a case involving both physiological activity and an underdeveloped art. When a patent applicant chooses to forego exemplification and bases utility on broad terminology and general allegations, they run the risk that unless one of ordinary skill in the art would accept the allegations as obviously valid and correct, the PTO may, properly, ask for evidence to substantiate them. Ex parte Sudilosky, 21 USPQ2d 1702, 1705 (BPAI 1991); In re Novak, 134 USPA 335 (CCPA 1962); In re Fouche, 169 USPQ 429 (CCPA 1971).
In essence, the specification (see, e.g., paragraphs 0033-37, 0040-45, 0051-53) merely presents an idea of, and leaves it entirely up to the practitioner to determine how to carry out the claimed methods. It has been established by legal decision that a patent is not a hunting license. It is not a reward for the search, but compensation for its successful conclusion. Tossing out the germ of an idea does not constitute an enabling disclosure. While every aspect of a generic claim need not have been carried out by an inventor or exemplified in the specification, reasonable detail must be provided in order to enable one of ordinary skill to understand and carry out the invention. It is true that a specification need not disclose what is well known in the art. However, that general, oft-repeated statement is merely a rule of supplementation, not a substitute for a basic enabling disclosure. It means that the omission of minor details does not cause a specification to fail to meet the enablement requirement under 35 U.S.C. 112(a) or 35 U.S.C. 112, first paragraph.
Absent specific guidance, one skilled in the art before the effective filing date of the claimed invention would not know how to practice the claimed invention and would require undue experimentation to practice over the full scope of the invention claimed.
The amount of experimentation necessary: The specification merely contains a speculative embodiments of the potential of mutated botulinum proteases to treat hypersecretory disorders at any “schedule effective” to reduce the secretory activity and leaves it entirely up to one of ordinary skill to determine which population or subpopulations of patients would be able to be treated for, e.g., hyperpituitarism or hypercortisolism, which administration route would be appropriate given a variety of factors and unpredictable nature of effective delivery, effective dosages of each composition in the disease populations, etc. One of ordinary skill in the art could not reasonably take these mere speculative embodiments and immediately apply it in the claimed methods. The specification offers no working examples or direction for treatment of any non-neuronal SNARE protein mediated disease (at any and all stages of the disease) in virtually any individual suffering from the disease(s) (e.g., an infant recently diagnosed with cystic fibrosis, a 19-year-old with hyperthyroidism, or a 63-year-old smoker who has been managing their COPD for 10 years, etc.) through administration of the claimed composition at any time. Nothing in the specification remotely demonstrates or suggests that the claimed compositions would have any efficacy against all of these exemplified disease states, because the specification does not have any data suggesting that the compositions were ever administered to a subject or subjects encompassed by the instant claims.
The essential elements toward validation of a therapeutic is the ability to test the drug (in this case, a composition having a protease with substrate specificity to non-neuronal SNARE proteins in a botulinum A toxin light chain) on subjects monitored during clinical symptoms of various disorders (e.g., hyperhidrosis, asthma, etc.), and link those results with subsequent histological confirmation of the presence, decrease, or absence of symptomology. This irrefutable link between antecedent drug and subsequent knowledge of treatment of the reaction is the essence of a valid treatment agent. All of this underscores the criticality of providing workable examples which are not disclosed in the specification for, e.g., treatment of non-neuronal SNARE disorders as instantly claimed.
For the reasons set forth above, one skilled in the art before the effective filing date of the claimed invention would not be able to make and/or use the invention as claimed. This is particularly true given the nature of the invention, the state of the prior art, the breadth of the claims, the amount of experimentation necessary, the level of skill which is high, the working examples provided and scarcity of guidance in the specification, and the unpredictable nature of the art. Thus, the claims are rejected under 35 U.S.C. 112(a) for failure to meet the enablement requirement.
Second rejection
Claims 1-5, 7, 10 and 18-19 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
A "representative number of species" means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. See AbbVie Deutschland GmbH & Co., KG v. Janssen Biotech, Inc., 759 F.3d 1285, 1300, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014). The issue is whether the skilled artisan would understand inventor to have invented, and been in possession of, the invention as claimed.
Claim interpretation: Claims 1-5, 7, 10 and 18-19 are drawn to “a method of treating an individual having a disease process mediated by a non-neuronal SNARE protein, comprising: providing a pharmaceutical comprising a synthetic peptide having a protease activity characterized by substrate specificity for the non-neuronal SNARE protein having an exosite, wherein the protease comprises a botulinum neurotoxin serotvpe A light chain comprising an exosite recognition sequence. wherein the exosite recognition sequence comprises a mutation at Glu148 of a wild-type botulinum toxin light chain, wherein the mutation comprises insertion of a non- native exosite recognition sequence interacts with the exosite of the non-neuronal SNARE protein, and wherein the mutation is selected to provide improved binding between the protease and the non-neuronal SNARE protein relative to binding of the protease to a neuronal SNARE protein that acts as a substrate for the wild-type botulinum toxin light chain; and administering the pharmaceutical to the individual on a schedule effective to reduce the secretory activity.” Under broadest reasonable interpretation, the claimed invention encompasses the use of a synthetic peptide pharmaceutical for the purpose of treating non-neuronal SNARE protein mediated diseases with the stipulation that the pharmaceutical (i.e., the peptide within the pharmaceutical) is mutated using a Glu148 point mutation and insertion of a non-native exosite recognition sequence while retaining the specific function(s) of improved binding between the protease and the non-neuronal SNARE protein relative to binding of the protease to a neuronal SNARE protein that acts as a substrate for the wild-type botulinum toxin light chain.
Claim 2 requires the “the synthetic peptide comprises a targeting moiety.” Claim 3 requires the “the targeting moiety binds to cells or tissues associated with the secretory activity”. Claim 4 requires that the targeting moiety supports binding of the synthetic peptide to a cell and transportation to the cell interior. Claim 5 requires the targeting moiety is selected from the group consisting of an antibody, and antibody fragment, a receptor ligand, a pharmaceutical compound, a microparticle, and an aptamer. Claim 7 requires the non-native exosite recognition sequence comprises one or more mutations to sites corresponding to Glu148 of SEQ ID NO. 4. Claim 10 requires that the mutation of Glul48 is selected from the group consisting of Met and Val. Claim 18 requires the non-neuronal SNARE protein is selected from the group consisting of SNAP-23. Finally, claim 19 requires the pharmaceutical composition to be administered via an injectable liquid, a topical preparation, a suspension, an ointment, a gel, a lotion, a cream, a patch configured for topical application, a film configured for topical application, a powder configured for inhalation, a vapor, a droplet mist, a sublingual drop, a lozenge, a nasal spray, an eye drop, a suppository, and a pessary.
The above claims have been interpreted under broadest reasonable interpretation to encompass the following: the treatment of any individual suffering from any non-neuronal SNARE protein mediated disease using a synthetic peptide with protease activity, including any mutation within Glu148 in a wild-type botulinum serotype A toxin light chain non-native exosite recognition sequence, capable of providing improved binding between the protease and any non-neuronal SNARE protein to reduce secretory activity, any targeting moiety capable of binding to any tissue or cell associated with secretory activity or binding of the peptide to a cell for transportation (claim 2-4), any antibody, fragment, receptor ligand, pharmaceutical compound, microparticle, or aptamer (claim 5), and the mutation of the amino acids at Glu148 in SEQ ID NO: 4 to any other amino acid (canonical or non-canonical) (see claim 7) for use in the claimed method.
The question at issue is whether the skilled artisan would have understood Applicant to be in possession of the massive genus of synthetic peptides, mutations within the peptides, targeting moieties, antibodies, fragments, receptor ligands, pharmaceutical compounds, microparticles, aptamers, etc. as instantly claimed.
Reduction to practice and disclosure of drawings or structural chemical formulas: Applicant has not reduced to practice anything in the specification that would lead one of ordinary skill to understand the identity of the synthetic peptides, mutations within the peptides, targeting moieties, antibodies, fragments, receptor ligands, pharmaceutical compounds, microparticles, aptamers, etc. that Applicant has defined solely by function for use in the claimed invention. Applicant has only reduced to practice 2 selected variants of botulinum neurotoxin A light chain that are mutated at Glu148 in SEQ ID NO: 4, and more specifically the substitutions of Glu148Arg and Glu148Lys as recited in Table 1 (see pg. 14 of the Specification; see paragraphs 0042-0045). However, none of these variants are demonstrated to perform the functions as instantly claimed. Applicant, further, has not reduced to practice any other mutants of botulinum A neurotoxin serotypes as broadly encompassed by the instant claims, including Glu148Met or Glu148Val as required by claim 10.
Applicant has only provided mere speculative embodiments of possible mutants/targeting moieties/etc. that could meet the claim limitations (see paragraphs 0030, 0043-44) discussing various identification strategies of LC/A mutations for substrate specificity for SNAP-23 and SNAP-29, targeting moieties (paragraph 0050), etc.
Sufficient, relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure: Applicant has not provided any information as to the defining structural characteristics that would lead one of ordinary skill in the art to the identity of diseased individuals, synthetic peptides, mutations within the peptides, targeting moieties, antibodies, fragments, receptor ligands, pharmaceutical compounds, microparticles, aptamers, BoNT serotypes, etc. that have the features as claimed that is then capable of being used as a treatment modality for the claimed genus of disorders. Applicants are claiming a massive genus of synthetic peptides, mutations within the peptides, targeting moieties, antibodies, fragments, receptor ligands, pharmaceutical compounds, microparticles, aptamers, etc., but fails to provide disclosure of specific physical, structural, biochemical properties required for the claimed invention, or any sufficient disclosure as to what any of these compositions would reasonably be.
For example, Chen (2012; Clinical Uses of Botulinum Neurotoxins: Current Indications, Limitations and Future Developments. Toxins, 4(10), 913-939; cited in IDS filed 05/09/2022) teaches that “botulinum neurotoxins (BoNTs) are organized into three functional domains: an N-terminal catalytic domain (light chain, LC), an internal translocation domain (heavy chain, HCT), and a C-terminal receptor binding domain (heavy chain, HCR). There are seven serotypes of BoNTs termed A–G. Each serotype of BoNT cleaves one of the SNARE proteins, VAMP2, SNAP25, or syntaxin 1a” (see pg. 913-914). Chen also specifically embodies a K224D mutated botulinum neurotoxin E light chain capable of cleaving SNAP23 and the natural substrate, SNAP25, but not SNAP29 or SNAP47. Upon direct protein delivery into cultured human epithelial cells, LC/E(K224D) cleaved endogenous SNAP23 so as to inhibit the secretion of mucin and IL-8 (i.e., the mutant has structure to perform Applicant’s claimed function) (see pg. 925, paragraph 1, and Fig. 4). While the art recognizes this specific botulinum light chain mutant for the claimed function of non-neuronal SNARE targeting, it still does not, and cannot, provide a nexus between this particular species of mutant and Applicant’s possession of the entire, massive genus of botulinum neurotoxin serotype A light chain mutants.
The composition, mutant botulinum serotype A toxin light chains, targeting moieties, etc., and method as claimed only reports the resulting effects of generally administering the composition. However, as the methods do not reasonably provide any indication as to how the results would reasonably be attained, it is also unclear as to how the functional limitations are attained. In essence, Applicants are describing a critical portion of their inventions by function. This is not sufficient to meet the written description requirement.
Thus, the lack of data and mere speculation throughout the specification cannot reasonably be extrapolated to and applied to support possession of the entire claimed genus of synthetic peptides, mutations within the peptides, targeting moieties, antibodies, fragments, receptor ligands, pharmaceutical compounds, microparticles, aptamers, etc. because no one species, combination, or variant accounts for the variability amongst the claimed genus. As in Ariad, merely drawing a fence around the outer limits of a purported genus is not an adequate substitute for describing a variety of materials constituting the genus and showing that one has invented a genus and not just a species.
The specification, then, is considered devoid of sufficiently detailed, relevant, identifying characteristics demonstrating that Applicant was in possession of the claimed genus of subject(s) in need thereof, i.e., additional complete or partial structures, other physical and/or chemical properties, functional characteristics coupled with a known or disclosed correlation between function and structure, or some combination thereof demonstrating possession of the claimed genus. Therefore, the claims are rejected under 35 U.S.C. 112(a) for lack of written description.
Response to Arguments
Applicant's arguments filed 01/09/2026 have been fully considered but they are not persuasive.
On pg. 8-10 of the remarks, Applicant argues that “The Office characterizes the application as a "hunting expedition" providing "only a germ of an idea" . . . [and] believes that this characterization is inaccurate. The specification of the application as filed does not merely recommend making random changes to a botulinum neurotoxin and hoping for the best. Rather, the Applicant describes a specific portion of the neurotoxin for modification- the region associated with exosite recognition. Moreover, the specification does not describe making random mutations within the specified region but rather cites not only specific amino acids but also specific substitutions for those amino acids. In view of this, the application as filed should not be considered a mere "hunting expedition". Applicant argues that the “claim is directed to methods of treating a disease mediated by a non-neuronal SNARE protein. This provides a clear boundary for a limited range of diseases and conditions, and falls within the scope of interfering with release of substances from target cells based on interference in non-neuronal SNARE protein function via administration of the mutated botulinum neurotoxins cited in the claim, claim 1 cites a limited range of diseases that falls within the scope of the application as filed, and notes that working examples are not a requirement for enablement.”
Applicant argues the claim requires “mutations at Glu148 of botulinum neurotoxin serotype A (BoNT/A) light chain, and has extensively characterized modifications in the protease substrate specificity of this protein on modification at this site”, shows the relative SNAP23 and 25 contents of chimeric peptide substrates, and that a series of BoNT/A LC mutations at Glu148 were prepared and screened for activity against these substrates which showed significant activity with chimeric peptide 3. From this, Applicant urges that Glu148 mutations renders the claim as sufficiently enabled because Glu148 lies within a portion of the light chain that is involved with exosite recognition and not catalysis.
In response, the examiner disagrees. First, while the examiner understands the mutation as claimed to be within the non-native exosite region (used for exosite recognition) as well as some site-specific mutants (see Table 1), this is not enough to provide sufficient enablement for treating a disease mediated by a non-neuronal SNARE protein. Applicant is broadly claiming (under broadest reasonable interpretation) the treatment of any individual suffering from any non-neuronal SNARE protein mediated disease using a synthetic peptide with protease activity, including any mutation within Glu148 in a wild-type botulinum serotype A toxin light chain non-native exosite recognition sequence, capable of providing improved binding between the protease and any non-neuronal SNARE protein to reduce secretory activity, any targeting moiety capable of binding to any tissue or cell associated with secretory activity or binding of the peptide to a cell for transportation (claim 2-4), any antibody, fragment, receptor ligand, pharmaceutical compound, microparticle, or aptamer (claim 5), and the mutation of the amino acids at Glu148 in SEQ ID NO: 4 to any other amino acid (canonical or non-canonical) (see claim 7) for use in the claimed method.
The diseases encompassed by the instant claim include disorders like abhorrent secretion of airway mucus, antibodies, insulin, gastric acids, and ions (including gastric hypersecretion, hyperhidrosis, asthma, COPD, cystic fibrosis, hyperthyroidism, hyperpituitarism, hypercortisolism, type 2 diabetes/insulin hypersecretion, etc). This claim limitation also encompasses the pharmaceutical being capable of producing a de minimis ability to provide improved binding between the protease and a non-neuronal SNARE protein, as well as reduced secretory activity by administering the pharmaceutical at essentially any time using any administration route. The state of the art at the time of filing (see rejection above), the extremely broad scope of the claims and lack of guidance in the specification exacerbates a highly unpredictable art. While any results presented in the art do not necessarily preclude Applicant’s hypotheses regarding treating an individual having diseases mediated by non-neuronal SNARE proteins using modified/mutated botulinum A neurotoxins, they certainly fail to support it in its totality that the claimed pharmaceutical is capable of the functions as instantly claimed.
Second, the examiner notes Applicant’s argument regarding working examples. However, the examiner pointed out in the above rejection that “[t]hough not controlling, the lack of working examples is, nevertheless, a factor to be considered in a case involving both physiological activity and an underdeveloped art. When a patent applicant chooses to forego exemplification and bases utility on broad terminology and general allegations, they run the risk that unless one of ordinary skill in the art would accept the allegations as obviously valid and correct, the PTO may, properly, ask for evidence to substantiate them. Ex parte Sudilosky, 21 USPQ2d 1702, 1705 (BPAI 1991); In re Novak, 134 USPA 335 (CCPA 1962); In re Fouche, 169 USPQ 429 (CCPA 1971).”
Finally, the examiner appreciates Applicant’s provided data in the remarks. However, the data provided does not provide the requisite nexus between Applicant’s claimed method and the validation of the claimed therapeutic. This requires the ability to test the drug (in this case, a composition having a protease with substrate specificity to non-neuronal SNARE proteins in a botulinum A toxin light chain) on subjects monitored during clinical symptoms of various disorders (e.g., hyperhidrosis, asthma, etc.), and link those results with subsequent histological confirmation of the presence, decrease, or absence of symptomology. This irrefutable link between antecedent drug and subsequent knowledge of treatment of the disease is the essence of a valid treatment agent.
The data provided does not suggest which point mutations at Glu148 is capable of the functions claimed. For example, none of the chimeras are labelled as to what the Glu residue was mutated to, nor does it provide evidence of administration of the synthetic peptide harboring the mutation(s) to treat any non-neuronal SNARE protein mediated disease. Furthermore, the specification only evidences the creation of 2 Glu148 mutants (Glu148Arg and Glu148Lys mutants), however the data provided seems to suggest the creation of at least 19 mutants (chimeras 1-6 and X1-13). It is suggested to Applicant to provide empirical evidence that would help clarify which specific Glu148 mutants, as argued on record, are capable of performing the method as instantly claimed.
On pg. 11-12 of the remarks, Applicant argues that genetic engineering methods for generating recombinant proteins are well-known and the application includes known methods that permit rapid screening of desired activities, generation of recombinant botulinum neurotoxins, specific regions for amino acid substitutions, etc. which can be performed by one of ordinary skill without highly specialized skills or laboratory robots suitably programmed.
In response, the examiner disagrees for much of the same reasons as set forth above (which will not be repeated here). While the examiner recognizes there are known methods for site-specific mutations and screening of recombinant proteins for desired activity, this alone is not sufficient to meet the enablement requirement. Thus, the rejection is maintained for the reasons set forth above.
On pg. 13-14 of the remarks, Applicant argues much of the same regarding the written description requirement. Applicant argues that the recitation of Glu148 mutation in BoNT/A light chain and that the embodiments provided in the specification are shown to have effect of enhancing cleavage of SNAP 23 containing peptides.
In response, the examiner disagrees. Applicant is broadly claiming using a synthetic peptide with protease activity, including any mutation within Glu148 in a wild-type botulinum serotype A toxin light chain non-native exosite recognition sequence, capable of providing improved binding between the protease and any non-neuronal SNARE protein to reduce secretory activity, any targeting moiety capable of binding to any tissue or cell associated with secretory activity or binding of the peptide to a cell for transportation (claim 2-4), any antibody, fragment, receptor ligand, pharmaceutical compound, microparticle, or aptamer (claim 5), and the mutation of the amino acids at Glu148 in SEQ ID NO: 4 to any other amino acid (canonical or non-canonical) (see claim 7). As further discussed in the rejection, Applicant has not reduced to practice anything in the specification that would lead one of ordinary skill to understand the identity of the synthetic peptides, mutations within the peptides, targeting moieties, antibodies, fragments, receptor ligands, pharmaceutical compounds, microparticles, aptamers, etc. that Applicant has defined solely by function for use in the claimed invention. Applicant has only reduced to practice 2 selected variants of botulinum neurotoxin A light chain that are mutated at Glu148 in SEQ ID NO: 4, and more specifically the substitutions of Glu148Arg and Glu148Lys as recited in Table 1 (see pg. 14 of the Specification; see paragraphs 0042-0045). However, none of these variants are demonstrated to perform the functions as instantly claimed. Applicant, further, has not reduced to practice any other mutants of botulinum A neurotoxin serotypes mutated at Glu148 as broadly encompassed by the instant claims, including Glu148Met or Glu148Val as required by claim 10. Thus, the claims lack written description and the rejection is maintained as set forth above.
Examiner’s Note
The examiner notes, for clarity of the record, that the prior art fails to adequately teach or suggest the use of a botulinum neurotoxin serotype A (harboring the claimed mutations) in a method for treating non-neuronal SNARE protein mediated disorders. The closest prior art of record is Chen (see rejections above) which discloses a K224D mutated botulinum neurotoxin E light chain capable of cleaving SNAP23 and the natural substrate, SNAP25, but not SNAP29 or SNAP47. Upon direct protein delivery into cultured human epithelial cells, LC/E(K224D) cleaved endogenous SNAP23 so as to inhibit the secretion of mucin and IL-8 (see pg. 925, paragraph 1, and Fig. 4).
Conclusion
NO CLAIMS ALLOWED.
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.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure:
Zhang et al. Abnormal expression of NSF, α-SNAP and SNAP23 in pulmonary arterial hypertension in rats treated with monocrotaline. Int J Clin Exp Med. 2015 Feb 15;8(2):1834-43.
Sprecher et al. A mutation in SNAP29, coding for a SNARE protein involved in intracellular trafficking, causes a novel neurocutaneous syndrome characterized by cerebral dysgenesis, neuropathy, ichthyosis, and palmoplantar keratoderma. Am J Hum Genet. 2005 Aug;77(2):242-51.
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/G.C.R./Examiner, Art Unit 1651
/THOMAS J. VISONE/Supervisory Patent Examiner, Art Unit 1672