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
The preliminary amendment filed 06/16/2023 is acknowledged. Claims 24-25 are canceled. Claims 1-23 are pending and under consideration.
Priority
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
The instant claims are entitled to the effective filing date of 12/17/2021, which is the filing date of PCT/KR2021/019302.
Specification
The disclosure is objected to because of the following informalities:
Page 45 line 21 references “Chapter 2 of the experimental materials and methods”, but chapter 2 is not referenced elsewhere in the specification. Therefore, “Chapter 2” should be replaced with either “section 2” to refer to the animal potency test 1-stability evaluation of botulinum toxin section, or the specification should specify which chapter 2 is being referenced.
Appropriate correction is required.
The use of the terms:
“Vaseline” page 30 line 3;
“Witepsol” page 32 line 4;
“Tween” page 32 line 2 and page 32 line 7;
“monolan” page 32 line 7;
“cebes” page 32 line 8;
“Adeps” page 32 line 8;
“Hydrokote” page 32 lines 9 and 10; and
“EDQM” page 45 line 14;
which are trade names or marks used in commerce, have been noted in this application. The terms should be accompanied by the generic terminologies; furthermore the terms should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Objections
Claims 20, 22 and 23 are objected to because of the following informalities:
Claims 20, 22 and 23 recite “Claim 1”, which should be lowercased to “claim 1” because the recitations are in middle of sentences.
Appropriate correction is required.
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.
Claims 20-23 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for treating or improving a neuromuscular related disease and preventing wrinkles, dystonia and/or spasticity, does not reasonably provide enablement for preventing any neuromuscular related disease. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected to use the invention commensurate in scope with these claims.
The factors to be considered in determining whether a disclosure would require undue experimentation include:
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, 8 USPQ2d, 1400 (CAFC 1988) and MPEP 2164.01.
The breadth of the claims and the nature of the invention:
Under the broadest reasonable interpretation, claims 20-23 entail preventing or treating any neuromuscular related disease. Specifically, claims 20-22 are drawn to compositions that prevent or treat any neuromuscular related disease, comprising botulinum toxin, hyaluronic acid or a pharmaceutically acceptable salt thereof; and one or more additives selected from the group consisting of sugars, non-ionic surfactants and stabilizers. Claim 23 is drawn to a method for preventing or treating any neuromuscular related disease comprising the step of administering a pharmaceutical composition to a subject in need thereof, wherein the pharmaceutical composition comprising botulinum toxin, hyaluronic acid or a pharmaceutically acceptable salt thereof; and one or more additives selected from the group consisting of sugars, non-ionic surfactants and stabilizers.
According to the instant specification, the neuromuscular-related diseases may be selected from a group consisting of headache, migraine, tension headache, sinus headache, cervicogenic headache, hyperhidrosis, axillary hyperhidrosis, palmar hyperhidrosis, plantar hyperhidrosis, Frey syndrome, hyperkinetic skin lines, facial wrinkles, forehead wrinkles, crow's feet, perioral wrinkles, nasolabial wrinkles, skin disorders, acne, rhinitis, sinusitis, achalasia, strabismus, chronic anal fissure, blepharospasm, musculoskeletal pain, foot pain, plantar fasciitis, fibromyalgia, pancreatitis, tachycardia, prostatic hypertrophy, prostatitis, urinary retention, urinary incontinence, overactive bladder, hemifacial spasm, tremor, muscle spasms, gastrointestinal disorders, diabetes, gout, sialorrhea, detrusor-sphincter dyssynergia, post-stroke spasticity, wound healing, cerebral palsy in children, smooth muscle spasms, restenosis, focal dystonia, epilepsy, cervical dystonia, thyroid disorders, hypercalcemia, obsessive-compulsive disorder, osteoarthritis, temporomandibular joint disorder, Raynaud's syndrome, striae distensae, peritoneal adhesions, vasospasm, rhinorrhea, muscle contractures, laryngeal dystonia, writer's cramp, and carpal tunnel syndrome, but is not limited thereto. See page 9.
The state of the prior art and the level of predictability in the art:
With respect to the state of the art on neuromuscular diseases, MedlinePlus (National Library of Medicine, 2018) discloses that there can be different causes for neuromuscular diseases. Many of them are genetic. Some neuromuscular disorders are autoimmune diseases. Sometimes the cause is unknown See page 1.
With respect to the state of the art on neuromuscular-related diseases [as defined above], Mayo Clinic (Obsessive-Compulsive disorder (OCD), 2023) discloses that there is no sure way to prevent obsessive-compulsive disorder. See page 6. OCD is a pattern of unwanted thoughts and fears known as obsessions. These obsessions lead to repetitive behaviors. See page 1. The causes aren’t fully understood. See page 5. Furthermore, the CDC (2024, May 14) discloses that in many cases the cause or causes of cerebral palsy before, during and after birth are not fully known, which means that currently little can be done to prevent it. Thus, Mayo Clinic and the CDC indicate that there are neuromuscular related diseases that cannot be prevented.
With respect to the state of the art on compositions for preventing or treating neuromuscular related diseases, Fink teaches a composition comprising (a) botulinum toxin and (b) non-crosslinked hyaluronic acid and its use for the treatment or prevention of dystonia, spasticity and/or wrinkles. See [0001] and claims 7-9. Fink teaches a composition for use in the treatment of diseases or conditions associated with hyperactive cholinergic innervation. See [0101]. Fink teaches exemplary diseases or conditions associated with hyperactive cholinergic innervation of muscles or exocrine glands, such as Frey syndrome, axillar hyperhidrosis, plantar hyperhidrosis, cerebral palsy, hemifacial spasm, tremor, bladder dysfunction, achalasia, sialorrhea, rhinorrhea, epilepsia, and anal fissures (e.g. examples of neuromuscular-related diseases). See [0104]. Fink suggests that muscle dystonia may be indicative of the hyperactive state. See [0102]. Fink teaches compositions for the use in the treatment of dystonia. See [0089], and [0095]. Dystonia can be differentiated into three types: focal dystonia, segmental dystonia and generalized dystonia. Examples of focal dystonia include laryngeal dystonia or cervical dystonia. See [0090]-[0094]. Thus, Fink teaches preventing dystonia, wrinkles and spasticity, and Fink teaches treating specific diseases or conditions, but Fink does not suggest using compositions comprising botulinum neurotoxin and non-crosslinked hyaluronic acid for preventing or treating any and all neuromuscular related diseases.
The amount of direction provided by the inventor and the existence of working examples:
The specification does not provide any working examples of preventing or treating a neuromuscular related disease. In example 1, the specification teaches screening various types of sugars and selecting lactose monohydrate and fructose as the final candidates. An animal potency test is performed after adding lactose monohydrate or fructose at different amounts to a botulinum toxin liquid composition. See page 45 lines 18-22. The test is conducted by injecting 0.1 mL of the liquid compositions into the abdominal cavity of ICR-mice. See page 44 lines 18-23. At week 0, compositions comprising lactose monohydrate at 0.1 w/v% cause 9/10 deaths, and compositions comprising fructose at 0.5 w/v% cause 9/10 deaths. See page 46 lines 1-10. For examples 2-3, similar processes are performed for botulinum toxin liquid compositions containing non-ionic surfactants and stabilizers respectively. Specifically, in example 2, polyoxyethylene (40) hydrogenated castor oil (HCO-40) is selected as the non-ionic surfactant and in example 3 glycerin is selected as the stabilizer. See page 46 lines 10-18 and page 47 lines 9-14. However, examples 1-3 do not specify whether hyaluronic acid or a salt thereof is included in the liquid botulinum toxin compositions, and the ICR-mice are not disclosed as being models for any neuromuscular related diseases. In examples 4 and 5, the additives fructose, HCO-40 and glycerin are mixed in various combinations with a botulinum toxin liquid comprising 1 MDa hyaluronic acid. See pages 48-49. In example 4, animal testing is conducted and the mouse mortality rates are measured during periods of 0, 3, 6, 10, 15, 20, 25 , 36 and 52 weeks. See page 49 and table 4. In example 5, the stabilization efficacy is confirmed. See pages 50-51. Yet, all working examples in the specification, i.e. examples 1-5, are silent regarding neuromuscular related diseases.
The quantity of experimentation needed to make or use the invention:
In view of the nature of the invention, the breadth of the claims, the guidance and
working examples in the specification, and the level of predictability within the art, as
evidenced above, one skilled in the art could not use the disclosed compositions to prevent all neuromuscular-related diseases, without undue experimentation. Prior to the effective filing date of the instantly claimed invention, it was well known that neuromuscular diseases may be genetically inherited, as evidenced by MedlinePlus. To date, there is no way to prevent the neuromuscular related diseases OCD and cerebral palsy in children, as evidenced by Mayo Clinic and the CDC respectively. Fink suggests that compositions comprising botulinum toxin and hyaluronic acid can be used to prevent wrinkles, spasticity and/or dystonia, and they can be used to treat specific diseases or conditions, but Fink does not suggest that such compositions can be used to prevent all neuromuscular related diseases.
Accordingly claims 20-23 are enabled for treating or improving a neuromuscular related disease and preventing wrinkles, spasticity and/or dystonia. However, the claims are not enabled for preventing all neuromuscular related diseases.
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 7, 9-10, 12-15 and 18 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.
In claims 7, 10, and 12-15, the parenthetical phrase "(w/v)" renders the claims indefinite because it is unclear whether the limitation within the parentheses is part of the claimed invention. For example, claim 7 requires the sugar to be at a concentration of 0.01 to 5 % (w/v) based on the total composition. However, it is unclear whether the “(w/v)” parenthetical phrase should be read into the claim, such that the concentration is limited to a w/v%. Alternatively, claim 7 may intend to encompass any %, such as w/w%, v/v% or w/v%. To obviate this rejection, the parentheses may be deleted from claims 7, 10, and 12-15.
Claim 9 requires the polyoxyethylene hydrogenated castor oil to have “a molar ratio of ethylene oxide of 10 to 60”, which is indefinite for two reasons. First, it is unclear whether ethylene oxide is required. According to the specification, castor oil to which ethylene oxide has been added by reacting castor oil with ethylene oxide can be used, wherein the ethylene oxide may be 10 to 60 mol based on 1 mol of castor oil. See page 19 lines 18-19. Therefore, claim 9 may require the non-ionic surfactant to be castor oil and ethylene oxide in a molar ratio of 10 to 60 based on 1 mol of castor oil; however, in this interpretation the non-ionic surfactant could not be polyoxyethylene hydrogenated castor oil because castor oil and ethylene oxide are distinct structures. Alternatively, claim 9 may intend to limit the molar ratio of the polyoxyethylene hydrogenated castor oil to ethylene oxide, such that the pharmaceutical liquid composition comprises polyoxyethylene hydrogenated castor oil as the non-ionic surfactant and further comprises ethylene oxide. Second, the 10 to 60 molar ratio required is unclear. In view of the specification, claim 9 may require the castor oil to ethylene oxide molar ratio to be 1:10, 1:11…1:60. Alternatively, claim 9 may require a “10 to 60” molar ratio, which can reasonably be interpreted as a 10:60 molar ratio. As such, one of ordinary skill in the art cannot ascertain the metes and bounds of the required non-ionic surfactant in claim 9.
Claims 13 recites “the sugar is either not comprised or is comprised at a concentration of 0.1 to 5 % (w/v) based on the total composition” and “the stabilizer is either not comprised or is comprised at a concentration of 0.1 to 10% (w/v) based on the total composition”. These limitations render claim 13 indefinite because it is unclear whether the sugar and stabilizer are required. In other words, there are multiple reasonable interpretations of the limitations. In the first interpretation, claim 13 requires the sugar and stabilizer to be present in the pharmaceutical liquid composition at any concentration, for example, the sugar may be at a concentration of 0.1 to 5% (w/v) and the stabilizer may be at a concentration of 0.1 to 10% (w/v). In the second interpretation, claim 13 encompasses pharmaceutical liquid compositions that do not include sugar and/or stabilizer. As such, one of ordinary skill in the art cannot ascertain the metes and bounds of the pharmaceutical liquid composition of claim 13.
Claim 14 recites “the non-ionic surfactant is either not comprised or is comprised at a concentration of 0.01 to 1% (w/v) based on the total composition; and the stabilizer is either not comprised or is comprised at a concentration of 0.1 to 10% (w/v) based on the total composition”. These limitations render claim 14 indefinite because it is unclear whether the non-ionic surfactant and stabilizer are required. In other words, there are multiple reasonable interpretations of the limitations. In the first interpretation, claim 14 requires the non-ionic surfactant and stabilizer to be present in the pharmaceutical liquid composition at any concentration, for example, the non-ionic surfactant may be at a concentration of 0.01 to 1% (w/v) and the stabilizer may be at a concentration of 0.1 to 10% (w/v). In the second interpretation, claim 14 encompasses pharmaceutical liquid compositions that do not include a non-ionic surfactant and/or a stabilizer. As such, one of ordinary skill in the art cannot ascertain the metes and bounds of the pharmaceutical liquid composition of claim 14.
Claim 15 recites “the sugar is either not comprised or is comprised at a concentration of 0.1 to 5 % (w/v) based on the total composition” and “the stabilizer is either not comprised or is comprised at a concentration of 0.1 to 1% (w/v) based on the total composition”. These limitations render claim 14 indefinite because it is unclear whether the sugar and stabilizer are required. In other words, there are multiple reasonable interpretations of the limitations. In the first interpretation, claim 15 requires the sugar and stabilizer to be present in the pharmaceutical liquid composition at any concentration, for example, the sugar may be at a concentration of 0.1 to 5% (w/v) and the stabilizer may be at a concentration of 0.1 to 1% (w/v). In the second interpretation, claim 15 encompasses pharmaceutical liquid compositions that do not include a sugar and/or a stabilizer. As such, one of ordinary skill in the art cannot ascertain the metes and bounds of the pharmaceutical liquid composition of claim 15.
Claims 18 is indefinite because it is a method claim that does not recite any active method steps. MPEP 2173.05(q) states that “attempts to claim a process without setting forth any steps involved in the process generally raises an issue of indefiniteness”. In the instant case, claim 18 requires a “method of maintaining the biological activity of botulinum toxin, utilizing a pharmaceutical liquid composition comprising the following (i) to (iii) as active ingredients”. However, the claim does not describe a way in which the pharmaceutical liquid composition is required to be utilized.
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 3 and 9 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 3 depends from claim 1 but does not clearly limit the pharmaceutical liquid composition of claim 1. Claim 3 recites “wherein the botulinum toxin is in a form that does not contain a complexing protein or is in a complex form containing a complexing protein”. Therefore, claim 3 encompasses botulinum toxin forms that do not contain a complexing protein and forms that do contain a complexing protein. Since claim 3 encompasses all forms of botulinum toxin, claim 3 does not clearly limit the botulinum toxin of claim 1.
Claim 9 does not clearly limit the non-ionic surfactant embodiment of claim 8 from which it depends. Claim 8 requires the non-ionic surfactant to be polyethylene hydrogenated castor oil. Claim 9 depends from claim 8 and requires the polyoxyethylene hydrogenated castor oil to have a molar ratio of ethylene oxide of 10 to 60. According to the specification, castor oil to which ethylene oxide has been added by reacting castor oil with ethylene oxide can be used, wherein the ethylene oxide may be 10 to 60 mol based on 1 mol of castor oil. See page 19 lines 18-19. Therefore, claim 9 may reasonably require the non-ionic surfactant to be castor oil and ethylene oxide in a molar ratio of 10 to 60 based on 1 mol of castor oil. This embodiment of claim 9 does not limit claim 8, because claim 8 requires the non-ionic surfactant to be polyoxyethylene hydrogenated castor oil.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1-18, and 20-22 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a natural product, which is a judicial exception, without significantly more. Each step described below is in reference to the subject matter eligibility test for products and processes (MPEP 2106).
Claims 1, 20 and 22 recite “composition ” in line 1. Therefore, claims 1-17, and 20-22 are directed to a composition of matter statutory category. Claim 18 recites a “method” in line 1, but does not recite any method steps. Therefore, under the broadest reasonable interpretation claim 18 is focused on a composition of matter because there is no difference in substance from a product claim. (Step 1:Yes).
Claims 1 recites a pharmaceutical liquid composition for long-term storage of botulinum toxin, comprising the following (i) to (iii) active ingredients: (i) botulinum toxin; (ii) hyaluronic acid or a pharmaceutically acceptable salt thereof; and (iii) one or more additives selected from the group consisting of sugars, non-ionic surfactants and stabilizers. Claims 2-17 depend from claim 1 and claims 18, and 20-22 require the same pharmaceutical composition as described in claim 1. Although the preamble of claim 1 indicates that the purpose of the composition is pharmaceutical, this aspect of the preamble does not limit the structure of the composition. See MPEP 2111.02(II) for preamble statements reciting purpose or intended use. Thus, claims 1-18 and 20-22 require a liquid composition comprising botulinum toxin, hyaluronic acid or a salt thereof and one or more additives selected from a group that consists of sugars, non-ionic surfactants and stabilizers. According to Mayo Clinic (Botulism - Symptoms and causes, 2022) when Clostridium botulinum bacteria get into a wound, they can multiply and make toxin. See the second paragraph on page 5. Hyaluronic acid is a gooey, slippery substance naturally produced by the body and can be found throughout the body, especially in eyes, joints and skin, as evidenced by Cleveland Clinic (Hyaluronic Acid: What It Is, Benefits, How to Use & Side Effects, 2022). See the first paragraph on page 1. Glycerin occurs naturally in fermented foods and beverages including honey, vinegar, wine and wine vinegar. See page 1 of Dumitrescu (What Is Glycerin? – IFIC, 2025). PubChem (National Center for Biotechnology Information, 2025) discloses that glycerin is distributed throughout blood. See page 3. Moreover, Shalev (eLife5:e21263, 2016) discloses that fructose is a simple sugar found in many fruits and plants. After it is eaten it enters the bloodstream. See pages 1 and 2. Thus, the evidence provided by Mayo clinic (2022), Cleveland Clinic, Dumitrescu, Pubchem and Shalev suggests that botulinum toxin, hyaluronic acid, and glycerin (e.g. stabilizer additive) and/or fructose (e.g. sugar additive) may be present in the blood of a topical wound infected by C. botulinum bacteria because C. botulinum produces toxin in an infected wound, skin includes gooey (e.g. fluid) hyaluronic acid and blood may include glycerin and/or fructose. For brevity, the blood of such wound will be referred to as an infected wound hereafter. Compared to the closest naturally occurring counterpart (e.g. infected wound), there is no structural difference between the instantly claimed liquid pharmaceutical product and the natural counterpart. Because there is no indication in the record that the instantly disclosed liquid pharmaceutical composition has a markedly different characteristic in structure, function, or other properties as compared to its natural counterpart (e.g. infected wound) claims 1-17 and 20-22 are directed to a natural-product, which is a judicial exception (Step 2A Prong 1: Yes).
The limitations in claims 1-2, 4-5, 7, 12 and 14 do not integrate the natural product into practical application. Claim 1 does not include any additional elements that could integrate the natural product (e.g. infected wound) into a practical application. Besides the natural product, claim 2 requires the botulinum toxin to be at a concentration of 5 to 40 units/mL. Claim 4 requires the hyaluronic acid to have a molecular weight of 30,000 to 5,000,000 Daltons. Claim 5 requires the hyaluronic acid to be at a concentration of 5-250 mg/mL. Claim 7 requires the sugar to be at a concentration of 0.01 to 5% (w/v), but does not limit the sugar structure or type of sugar in anyway. Claim 12 requires the stabilizer to be at a concentration of 0.1 to 10% (w/v), but does not limit the stabilizer structure or type of stabilizer in anyway. Claim 14 requires the hyaluronic acid to have a molecular weight between 500,000 to 2,000,00 Da, and the sugar to be at a concentration of 0.1 to 5% (w/v). The limitations of claims 2, 4-5, 7, 12 and 14 do not include elements that could integrate the natural product into a practical application because each claim merely describes characteristics of the natural product, which serves to generally link the natural product to its field of use as a pharmaceutical.
The limitations of claims 3, 6, 8-11, 13 and 15-17 do not integrate the natural product into practical application. Claim 3 cannot integrate the natural product into a practical application because claim 3 encompasses all forms of botulinum toxin. Claim 6 requires the sugar to be lactose monohydrate or fructose. Claim 11 requires the stabilizer to be glycerin. Yet, claims 6 and 11 merely describe the fructose and/or glycerin containing natural product discussed. As such, the limitations of claims 6 and 11 do not add an element to the judicial exception that could integrate it into a practical application. Claim 8 requires the non-ionic surfactant to be polyoxyethylene hydrogenated castor oil (HCO); and claim 9 requires the HCO to have an ethylene oxide molar ratio of 10 to 60. The limitations of claims 8 and 9 do not integrate the natural product into a practical application because the claims encompass compositions with trace amounts of the HCO. As such, claims 8 and 9 merely imply that the composition can contain additional elements besides the judicial exception. Claim 10 limits the concentration of the non-ionic surfactant to 0.01 to 1% (w/v), but claim 10 does not limit the structure of the non-ionic surfactant. Therefore, the limitation is insignificant because it provides insufficient specificity to meaningfully limit the composition. Claim 13 and 15 limit the molecular weight of the hyaluronic acid to 5,00, 000 to 2,000,000 Da or 2,500,000 to 5,000,000 Da respectively, and require the concentration of the non-ionic surfactant to be 0.01 to 1% (w/v). These limitations of claims 13 and 15 do not integrate the natural product into a practical application because the molecular weight limitation of the hyaluronic acid merely serves to generally link the product to its use as a pharmaceutical, and the non-ionic surfactant limitation is recited at a high level of generality such that encompasses any non-ionic surfactant, as long as it is present at the required concentration. Claim 16 requires the composition to further comprise sodium phosphate as a buffer at a concentration of 25 to 100 mM. However, sodium phosphate refers to a variety of salts derived from sodium and phosphate. Support for this interpretation of sodium phosphate can be found in Noah Chemicals (2023) page 1 paragraph 1. Therefore, the limitation of claim 16 is insignificant because it merely implies that the composition can contain additional elements besides the judicial exception. Claim 17 requires the composition to be a ready-to-use injectable formulation, but does not explicitly limit the structure of the liquid composition. As such, the limitation merely serves to generally link the composition to its field of use as a pharmaceutical. Thus, claims 3, 6, 11, and 17 do not add any elements that could integrate the natural product into a practical application; and the additional elements of claims 8-10, 13 and 15 are insignificant.
Claim 18 does not add any structural elements to the judicial exception, nor does claim 18 require an active method step that could integrate it into a practical application. Claim 18 recites a “a method of maintaining the biological activity of botulinum toxin, utilizing a pharmaceutical liquid composition”. The pharmaceutical liquid composition of claim 18 is identical to that of claim 1, and the way in which the pharmaceutical liquid composition is required to be utilized is not limited. Therefore, claim 18 is directed to a natural product and seeks to tie up all use of the natural product.
Claims 20-22 require the liquid composition of claim 1 to be used for preventing or treating/improving a neuromuscular related disease. Claim 21 limits the neuromuscular related disease. The limitations of claims 20-22 do not add any elements to the natural product. Rather, the limitations merely serve to generally link the composition to its use as a pharmaceutical.
Accumulatively, the limitations or additional elements of claims 1-18 and 20-22 taken as a whole do not integrate the judicial exception into a practical application (Step 2A Prong 2: No).
The additional elements fail to amount to an inventive concept. Zhang (US 2020/0370031, published Nov. 16, 2020) teaches a multilayer nano-cell comprising: an innermost oil phase core including biomolecules in an oil, the biomolecules including botulinum neurotoxin; a first layer including a water phase layer encapsulating the innermost oil phase core, a second layer including an oil phase layer encapsulating the first layer. See claim 12. The oil phase mixture includes at least one selected from a list that includes PEG-40 hydrogenated castor oil (e.g. a non-ionic surfactant). See claim 16. The water phase layer in the first layer further includes one or more selected from a list that includes hyaluronic acid. See claim 19. Therefore, compositions comprising botulinum toxin, hyaluronic acid and PEG-40 hydrogenated castor oil were well known prior to the effective filing date, as evidenced by Zhang. Furthermore, Jang teaches a pharmaceutical composition for treating a foot pain comprising hyaluronic acid or a pharmaceutically acceptable salt thereof, and botulinum toxin. See claim 1. In example 1, Jang teaches dissolving hyaluronic acid (HA) in 50 mM sodium phosphate buffer and mixing in botulinum toxin A. See [0054]. Furthermore Jang teaches carriers such as sucrose (e.g. sugar additive). See [0038]. As such, the additional limitations in the claims do not amount to an inventive concept in view of conventional and well-understood practices in the prior art (Step 2B: No).
For all of these reasons, claims 1-18 and 20-22 are not patent eligible.
Claim Interpretation
Claim 9 is interpreted as requiring the polyoxyethylene hydrogenated castor oil to be prepared by the result of 1 castor oil mole to 10 to 60 ethylene oxide moles. For example, the instant specification discloses that polyoxyethylene (40) hydrogenated castor oil is obtained by addition polymerization through adding 40 mol of ethylene oxide to hydrogenated (i.e., hydrogen-added) castor oil. See page 19 lines 20-22. Thus, polyoxyethylene (40) hydrogenated castor oil is interpreted as having an ethylene oxide ratio between 10 to 60.
Claim 13 requires the pharmaceutical liquid composition to comprise the hyaluronic acid at a molecular weight of 500,000 to 2,000,000 Daltons and the non-ionic surfactant at a concentration of 0.01 to 1% w/v.
Claim 14 requires the pharmaceutical liquid composition to comprise the hyaluronic acid at a molecular weight between 500,000 to 2,000,000 Daltons, and sugar at a concentration of 0.1 to 5% w/v based on the total composition.
Claim 15 requires the pharmaceutical liquid composition to comprise the hyaluronic acid at a molecular weight between 2,500,000 to 5,000,000 Daltons, and the non-ionic surfactant at a concentration of 0.01 to 1% w/v based on the total composition.
Claim 17 requires the pharmaceutical composition of claim 1 to be in an injectable formulation, and any injectable formulation is considered to be ready-to-use.
Claim 18 is interpreted as requiring the structure of a pharmaceutical liquid composition comprising botulinum toxin; hyaluronic acid or its pharmaceutically acceptable salt; and one or more additives selected from the group consisting of sugar, non-ionic surfactant and stabilizer. As such, the composition is identical to that of instant claim 1.
Claims 19 and 20 are product claims that require the structure of the pharmaceutical liquid composition of claim 1. Claim 20 indicates that the purpose or intended-use of the pharmaceutical liquid composition of claim 1 is to be used as an active ingredient in a pharmaceutical composition for preventing or treating a neuromuscular related disease.
Claims 20-22 require the structure of the pharmaceutical liquid composition according to claim 1. The intended uses recited in claims 20-22 do not structurally limit the composition. A “neuromuscular related disease” is interpreted as encompassing at any neuromuscular related diseases, such as the ones recited in claim 21.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1, 3, 11, and 17-22 is/are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Fink (US 2019/0060422).
Regarding claims 1, 11 and 18, Fink teaches preparing two subunits of a composition. Subunit 1 includes a lyophilisate [sic. lyophilizate] containing 50 units of botulinum neurotoxin type A, 25 mg human serum albumin (HSA) and 1.18 mg sucrose (e.g. sugar additive) reconstituted with 1 ml of 0.9 % saline. See example 1, [0120]-[0121]. Subunit 2 includes a solution containing 1 ml water, 14 mg non-crosslinked hyaluronic acid having an average molecular weight of about 3.8 kD, 34 mg mannitol, 3.0 mg glycerine [sic. glycerin] (e.g. stabilizer additive), 0.6 mg of phosphate buffer is provided. See [0122]. The subunits are mixed such that one ml of the resulting aqueous composition (e.g. liquid composition) each contains: 25 units botulinum neurotoxin A, 7 mg non-crosslinked hyaluronic acid, sucrose and glycerin. See [0123]. Fink teaches a composition comprising a) botulinum neurotoxin, b) non-crosslinked hyaluronic acid having an average molecular weight of 2.5 MDa to 4.5 MDa. See claim 1. The composition further comprises salt, optionally a neurotoxin stabilizing agent, crystallization inhibitor, buffer and/or radical scavenging agent. See claim 5. Thus, Fink teaches a liquid aqueous composition in example 1 comprising botulinum toxin, hyaluronic acid, a sucrose sugar additive, and a glycerin stabilizer additive.
Regarding claim 3, Fink teaches botulinum toxin complexes present in the form of high-molecular protein complexes comprising two components; namely the paralytically acting neurotoxin component and an associated non-toxic bacterial protein component which can be regarded as a coat protein including hemagglutinin and non-hemagglutinin proteins. The high molecular weight of the botulinum toxin complexes varies among the distinct botulinum toxin serotypes. See [0003]. Fink teaches a botulinum neurotoxin type A complex that preferably comprises a neurotoxin component of about 150 kDa, which can be split into a light chain and heavy chain and optionally one or more coat proteins such as hemagglutinin or non-haemagglutinin. See [0019].
Regarding claim 17, Fink teaches injecting two groups of 10 mice each into the right gastrocnemius muscle with 0.8ml of the composition according to the reference example or with 1.6 ml of the composition according to example 1. See [0126]. In example 1, Fink teaches mixing subunits such that one ml of the resulting aqueous composition contains botulinum neurotoxin type A, non-crosslinked hyaluronic acid, sucrose and glycerin. See [0123]. Thus, Fink indicates that the composition of example 1 is in an injectable formulation.
Regarding claim 19, Fink teaches preparing two subunits of a composition. Subunit 1 includes a lyophilisate containing 50 units of botulinum neurotoxin type A , 25 mg human serum albumin (HSA) and 1.18 mg sucrose (e.g. sugar additive) were reconstituted with 1 ml of 0.9 % saline. See example 1, [0120]-[0121]. Subunit 2 includes a solution containing 1 ml water, 14 mg non-crosslinked hyaluronic acid having an average molecular weight of about 3.8 kD, 34 mg mannitol , 3.0 mg glycerine [sic. glycerin] (e.g. stabilizer additive), 0.6 mg of phosphate buffer is provided. See [0122]. The subunits are mixed such that one ml of the resulting aqueous composition (e.g. liquid composition) each contains: 25 units botulinum neurotoxin A, 7 mg non-crosslinked hyaluronic acid, sucrose and glycerine. See [0123].
Regarding claims 20-21, Fink teaches an aqueous composition that contains: 25 units botulinum neurotoxin A, 7 mg non-crosslinked hyaluronic acid, sucrose and glycerine. See [0123]. Fink teaches a composition comprising a) botulinum neurotoxin, b) non-crosslinked hyaluronic acid having an average molecular weight of 2.5 MDa to 4.5 MDa. See claim 1. The composition further comprises salt, optionally a neurotoxin stabilizing agent, crystallization inhibitor, buffer and/or radical scavenging agent. See claim 5. Fink teaches a composition for use in the treatment of diseases or conditions associated with hyperactive cholinergic innervation. See [0101]. Fink teaches exemplary diseases or conditions associated with hyperactive cholinergic innervation of muscles or exocrine glands, such as Frey syndrome, axillar hyperhidrosis, plantar hyperhidrosis, cerebral palsy, hemifacial spasm, tremor, bladder dysfunction, achalasia, sialorrhea, rhinorrhea, epilepsia, and anal fissures (e.g. examples of neuromuscular-related diseases). See [0104]. Fink teaches cosmetically smoothing or preventing wrinkles. See [0110]. Examples of wrinkles are crow’s feet, perioral wrinkles, forehead creases (e.g. forehead wrinkles), nasolabial folds (e.g. nasolabial wrinkles). See [0113]. Fink teaches a composition for treatment of dystonia. See [0089]. Examples of focal dystonia are laryngeal dystonia or cervical dystonia, wherein cervical dystonia might be also considered blepharospasm. See [0094].
Regarding claim 22, Fink teaches an aqueous composition that contains: 25 units botulinum neurotoxin A, 7 mg non-crosslinked hyaluronic acid, sucrose and glycerine. See [0123]. Fink teaches a composition comprising a) botulinum neurotoxin, b) non-crosslinked hyaluronic acid having an average molecular weight of 2.5 MDa to 4.5 MDa. See claim 1. The composition further comprises salt, optionally a neurotoxin stabilizing agent, crystallization inhibitor, buffer and/or radical scavenging agent. See claim 5. Fink teaches the cosmetic use of a composition for smoothing or preventing wrinkles. See [0110] and [0117]. Fink teaches a composition for use in the treatment of diseases or conditions associated with hyperactive cholinergic innervation. See [0101]. Fink teaches exemplary diseases or conditions associated with hyperactive cholinergic innervation of muscles or exocrine glands, such as Frey syndrome, axillar hyperhidrosis, plantar hyperhidrosis, cerebral palsy, hemifacial spasm, tremor, bladder dysfunction, achalasia, sialorrhea, rhinorrhea, epilepsia, and anal fissures (e.g. examples of neuromuscular-related diseases). See [0104]. Thus, Fink teaches cosmetic composition for treating neuromuscular related diseases.
Claim Rejections - 35 USC § 103
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.
Claim(s) 2, 4-7, 12, 14, and 23 is/are rejected under 35 U.S.C. 103 as being unpatentable over Fink (US 2019/0060422).
The teachings of Fink with respect to instant claim 1 are discussed above.
Regarding claim 2, Fink teaches mixing subunits such that one ml of the resulting aqueous composition each contains 25 units botulinum neurotoxin A, non-crosslinked hyaluronic acid, glycerine [sic. glycerin] (e.g. stabilizer) and sucrose (e.g. sugar). See [0123] and the table. Fink teaches a preferable concentration range of 20 to 40 units of botulinum neurotoxin, preferably botulinum neurotoxin type A per ml. See [0060]-[0061]. Thus, Fink teaches a botulinum toxin concentration that overlaps with the instantly claimed 5 to 40 units/mL range.
Fink does not teach botulinum toxin at a concentration of 5 to 40 units/mL based on the total composition.
It would have been obvious to a person of ordinary skill in the art prior to the effective filing date of the instantly claimed invention to optimize the workable concentration range of the botulinum toxin in the aqueous composition of Fink. A person of ordinary skill in the art has good reason to pursue the known options. There would be a reasonable expectation of success because Fink teaches a botulinum neurotoxin type A concentration range of 20 to 40 units per ml, which overlaps with the instantly claimed concentration range of 5 to 40 units/mL. MPEP 2144.05(II) indicates that differences in concentration generally amount to “routine optimization” and will not support patentability unless there is evidence indicating the claimed feature is critical. “Where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955).
Regarding claim 4, Fink teaches non-crosslinked hyaluronic acid having an average molecular weight of 2.5 MDa to 4.5 MDa (i.e. 2,500,000-4,500,000 Daltons), which overlaps with the instantly claimed range of 30,000-5,000,000 Da. See claim 1 of Fink and paragraphs [0009], [0011], and [0026]. In example 1, Fink teaches subunit 2, which includes 14 mg non-crosslinked hyaluronic acid having an average molecular weight of about 3.8kD. See [0122]. Furthermore, Fink teaches mixing subunits such that the resulting aqueous composition contains: non-crosslinked hyaluronic acid, botulinum neurotoxin type A, glycerine [sic. glycerin] (e.g. stabilizer) and sucrose (e.g. sugar). See [0123].
Fink does not explicitly teach hyaluronic acid with a molecular weight of 30,000 to 5,000,000.
It would have been obvious to a person of ordinary skill in the art prior to the effective filing date of the instantly claimed invention to optimize the workable molecular weight range of the non-crosslinked hyaluronic acid. A person of ordinary skill in the art has good reason to pursue the known options. There would be a reasonable expectation of success because Fink teaches non-crosslinked hyaluronic acid with an average molecular weight of 2,500,000-4,500,000 Daltons, which overlaps with the instantly claimed weight range. MPEP 2144.05(II) states that “[w]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955).
Regarding claim 5, Fink, in example 1 teaches mixing subunits such that one ml of the resulting aqueous composition contains 7 mg non-crosslinked hyaluronic acid (i.e. 7mg/ml), botulinum neurotoxin type A, glycerine [sic. glycerin] (e.g. stabilizer) and sucrose (e.g. sugar). See [0123]. Fink teaches an aqueous composition that preferably includes non-crosslinked hyaluronic acid at a concentration of 2.5 to 9 mg. See [0060] and [0070].
Fink does not explicitly teach hyaluronic acid at a concentration of 5 to 250 mg/mL based on the total composition.
It would have been obvious to a person of ordinary skill in the art prior to the effective filing date of the instantly claimed invention to optimize the workable concentration range of the non-crosslinked hyaluronic acid. A person of ordinary skill in the art has good reason to pursue the known options. There would be a reasonable expectation of success because Fink teaches an aqueous composition comprising non-crosslinked hyaluronic acid at a concentration of 7mg/mL, which is within the instantly claimed concentration range. MPEP 2144.05(II) indicates that differences in concentration generally amount to “routine optimization” and will not support patentability unless there is evidence indicating the claimed feature is critical. “Where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955).
Regarding claim 6, in example 1, Fink teaches an aqueous composition comprising botulinum neurotoxin type A, non-crosslinked hyaluronic acid, glycerine [sic. glycerin] (e.g. stabilizer) and 0.59 mg of sucrose. See [00123]. Furthermore, Fink teaches examples of crystallization inhibitors, such as fructose and sucrose. See [0048].
It would have been obvious to a person of ordinary skill in the art prior to the effective filing date of the instantly claimed invention to replace the sucrose in the aqueous composition in example 1 of Fink with the fructose. Doing so is merely substituting known crystallization inhibitors. There would be a reasonable expectation of success because Fink suggests that sucrose and fructose are interchangeable.
Regarding claim 7, Fink teaches an aqueous composition that preferably includes a crystallization inhibitor at 0.04 to 0.094% w/v. See [0060] and [0064]. Fink teaches examples of crystallization inhibitors, such as fructose and sucrose. See [0048]. In example 1, Fink teaches an aqueous composition comprising botulinum neurotoxin type A, non-crosslinked hyaluronic acid, glycerine [sic. glycerin] (e.g. stabilizer) and 0.59 mg of sucrose. See [00123].
Fink does not explicitly teach a sugar at a concentration of 0.01 to 5 % (w/v) based on the total composition.
It would have been obvious to a person of ordinary skill in the art prior to the effective filing date of the instantly claimed invention to optimize the workable crystallization inhibitor concentration range. A person of ordinary skill in the art has good reason to pursue the known options. There would be a reasonable expectation of success because Fink teaches a crystallization inhibitor concentration range of 0.04 to 0.0