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 .
Priority
The present application claims priority to the applications, 63/174,415 and PCT/US2022/024684, with effective filing dates of 13 April 2021 and 13 April 2022, respectively.
Claim Status
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 29 July 2026 has been entered.
This Office Action is in response to Applicant’s Amendment filed, 29 July 2026, wherein the Applicant amended claims 2-5. Support for the amendment is found in claim 1. Claim 21 was previously canceled.
Claims 1-20 are pending.
Information Disclosure Statement
The Information Disclosure Statement filed on 29 July 2026 and the references cited
therein have been considered, unless indicated otherwise.
Claim Interpretation
For clarity, the Examiner notes that the specification defines “treating” refers to an approach for obtaining beneficial or desired results including but not limited to therapeutic benefit and/or prophylactic benefit ([0068]). The specification further specifies that for prophylactic benefit, the compositions are administered to a patient at risk of developing a particular disease, or to a patient reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease has not yet been made ([0068]).
Rejections Withdrawn
Claim Rejections – Double Patenting
1. Claims 1-20 were rejected on the ground of nonstatutory double patenting as being unpatentable over claims 12-16 and 23-26 of U.S. Patent No. 12,565,501. Applicant’s arguments and Rule 1.132 Declaration, see pages 12-16, have been fully considered and are persuasive. The nonstatutory double patenting rejection of claims 1-20 has been withdrawn.
Rejections New
Claim Rejections – 35 U.S.C. 112
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.
2. Claim 7-19 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 a method of non-prophylactically treating a neurodegenerative disorder, a demyelinating disease, and a neuropathic disease in a subject, does not reasonably provide enablement for a method of preventing a neurodegenerative disorder, a demyelinating disease, or a neuropathic 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 criteria for enablement set out in the In re Wands, MPEP § 2164.01(a), considers the following factors:
Breadth of the claims
The instant claims are directed to a method of treating or preventing a neurodegenerative disorder, a demyelinating disease, and a neuropathic disease in a subject via administering a polymorph of
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. Thus, encompassing all neurodegenerative disorders, demyelinating disease, and neuropathic diseases and prevention thereof. The Examiner also notes that paragraph [0068] on pages 11-12 of the specification filed on October 6, 2023 defines as, "treatment" or "treating" or "palliating" or "ameliorating" are used interchangeably herein. These terms refer to an approach for obtaining beneficial or desired results including but not limited to therapeutic benefit and/or prophylactic benefit. Thus, the claimed methods encompass both therapeutic and prophylactic treatments. Applicant also indicates in paragraph [0067] that subject or patient encompasses mammals.
As such, the breadth of the claims is great.
Level of Skill in the Art
The level of skill in the art is a clinician or an artisan with a PhD.
State of the Prior Art
Lebois (ACS Chem. Neurosci., 2017, 8, 1177-1187) teaches that Alzheimer’s is a progressive, neurodegenerative disease, which is the most common cause of dementia worldwide and accounts for 60-70% of all cases of dementia (page 1177, column 1, paragraph 1). Lebois teaches that there is no single disease-modifying available therapy for Alzheimer’s patients that slows or prevents the course of the disease (page 1177, column 1, paragraph 1). Lebois teaches that while many anti-amyloid therapies have shown promising effects in mouse models of Alzheimer’s, none have translated into an effective therapy in human Alzheimer’s patients (page 1177, column 1, paragraph 1). Additionally, Lebois teaches that there is an unmet need for therapies with both symptomatic and disease-modifying effects for individuals with mild cognitive deficits or early-stage dementia (page 1177, column 2, paragraph 1). Lebois teaches that there are two FDA-approved therapies for Alzheimer’s: donepezil (an acetylcholine esterase inhibitor) and memantine (NMDAR antagonist), both of which only provide modest symptomatic effects (page 1177, column 2, paragraph 2). Lebois teaches that cholinergic neurotransmission is complex, whereby acetylcholine acts on multiple subtypes of both nicotinic and muscarinic acetylcholine receptors to mediate its effects (many of which functionally oppose one another) and thus it is not surprising that nonselective activators (e.g. donepezil) suffer from modest efficacy and dose-limiting side effects (page 1177, column 2, paragraph 2; page 1178, column 1, paragraph 1). Lebois teaches evaluating acetylcholine M1 receptor as a neuroprotective target for Alzheimer’s therapy (page 1178, column 2, paragraph 2). Lebois teaches that the failure of all disease-modifying clinical trials to date, along with the recognition that disease pathology begins 20 or more years prior to the onset of clinical symptoms has produced a paradigm-shift in Alzheimer’s treatment efforts (page 1178, column 2, paragraph 2). Lebois teaches that the field is increasingly focused on earlier intervention, including in asymptomatic individuals with pathology already present (i.e. secondary prevention) and individual with mild cognitive impairment due to Alzheimer’s (page 1178, column 2, paragraph 2; page 1179, column 1, paragraph 1). Lebois teaches designing a preventive treatment trial that models asymptomatic individuals with pathology already present (i.e. secondary prevention) and individuals with mild cognitive impairment due to Alzheimer’s via dosing the small molecule, VU0364572 to mice (page 1178, column 2, paragraph 2; page 1179, column 1, paragraph 1). Lebois teaches that chronic activation of M1 via with the selective M1 agonist, VU0364572, protects against neuropathology and prevents memory impairments from forming in an aggressive 5XFAD mouse model of Alzheimer’s (page 1182, column 2, paragraph 2). However, Lebois teaches that the preventive efficacy in an aggressive rodent Alzheimer’s model may offer higher translational potential. Additionally, Lebois teaches that there was no observed evidence of a VU0364572-mediated benefit in reversing contextual fear conditioning deficits at the dose tested and that cued fear conditioning is a sensitive test of amygdala function with involvement of the hippocampus (page 1182, column 2, paragraph 4; page 1183, column 1, paragraph 1).
Leenaars (J. Transl. Med., 2019, 17(223), 1-22) teaches that current drug development is handicapped by high attrition rates and that many molecules that were promising during preclinical development fail during subsequent clinical testing (page 1, column 1, paragraph 1). Leenaars further teaches that animals and humans are complex systems and therefore always unpredictable (page 2, column 1, paragraph 1), which further underscores the unpredictability of the art and translation of promising candidate from in vitro models to in vivo models and beyond into humans.
Mullard (Nature News & Analysis, 2020, 226) teaches that the recent failure of a phase II/III trial of amyloid antibodies in people with or at risk of inherited early-onset Alzheimer’s has dealt another blow to the dementia pipeline (paragraph 1). Mullard teaches that repeated failures of amyloid-modulating drugs in patients with mild and prodromal disease turned researchers toward long-term use of these drugs before the onset of disease to improve outcomes (paragraph 2). Mullard teaches that in a preventive trial testing prevention with Lilly’s solanezumab or Roche’s gantenerumab in patients who within 15 years of the expected age of disease onset or showing mild signs of memory loss, treatment did not slow down memory loss or cognitive decline (paragraph 2). Additionally, Mullard teaches that Amgen and Novartis halted two phase III trials of the BACE1 inhibitor, umibecestat, as a monotherapy and in combination with the amyloid vaccine CAD103 in high-risk patients recruited before the onset of cognitive impairment (paragraph 3).
Lowe (“Muscarinic Agonists Come Back Around,” In the Pipeline¸ 2016, < science.org/content/blog-post/muscarinic-agonists-come-back-around>, accessed 14 Sept 2026) teaches that Allergan partnered with Heptares to develop selective muscarinic modulation, which could be useful in Alzheimer’s and several other CNS (central nervous system) diseases (page 1, paragraph 1). Lowe teaches that selectively modulating muscarinic M1 receptor is not easy to attain and that the side effects will hammer you if selectivity is not achieved (page 1, paragraph 2). Lowe teaches that there is more to the mechanism of a selective M1 agonist than simple replacement (page 1, paragraph 3). Lowe teaches that the motivation for a selective M1 agonist is to increase the tone of the whole signaling network priming postsynaptic neurons to be able to respond to lower doses of acetylcholine from across the synapse and that the whole cholinergic system is known to be hit pretty hard by Alzheimer’s (page 1, paragraph 3-4). Lowe teaches that there is a worry in pharma about selective M1 modulation in that without a disease-altering mechanism, then one would be boarding a sinking ship by going after cholinergic neurons (page 1, paragraph 4). Lowe teaches that donepezil inhibits acetylcholine breakdown in the synapse and does not work that well but that there is still hope from the efficacy seen with donepezil, which is mildly palliative at best and goes away after a period of treatment (page 1, paragraphs 4-5).
Welliver (J. Neurosci.¸2018, 38(31), 6921-6932) teaches that regenerative therapies that promote remyelination in multiple sclerosis (MS) have the potential to restore lost neurological function and prevent chronic demyelination-associated disease progression (page 6921, column 1, paragraph 1; page 6921, column 2, paragraph 1). Welliver teaches that remyelination acts to protect the demyelinated axons and that approaches that accelerate remyelination will yield additional functional benefits by acting to prevent the progressive neurodegeneration that is associated with chronic demyelination (page 6922, column 1, paragraph 1). Welliver teaches that nonselective muscarinic receptor antagonists have been shown to improved remyelination in rodents but that current drugs have potent activity for other receptors (page 6922, column 1, paragraph 2). Welliver teaches that for success of future therapy, it is critical to determine which MR subtype or subtypes signal to block oligodendrocyte differentiation and inhibit repair (page 6922, column 1, paragraph 2). Welliver teaches that solifenacin, an M1/3R selective antagonist, induced oligodendrocyte differentiation in a mouse model of hypomyelination (page 6922, column 1, paragraph 3).
Healthline (“Is it possible to prevent multiple sclerosis,” Healthline, 2025, < healthline.com/health/multiple-sclerosis-prevention#takeaway>, accessed 14 Sept 2026) teaches that MS is a disease of the central nervous system (page 2, paragraph 2). Healthline teaches that MS cannot be prevented and that certain risk factors cannot be modified but that changing diet and lifestyle may help reduce the risk of developing MS (page 7, paragraphs 1-2).
Cleveland Clinic (“Neuropathic Pain,” Cleveland Clinic, 2026, < my.clevelandclinic.org/health/diseases/15833-neuropathic-pain>, accessed 14 Sept 2026) teaches that neuropathic pain can be mild or severe and that it can be caused by central nervous system disorders (page 1, paragraph 1). Cleveland Clinic teaches that neuropathic pain can happen if the nervous system malfunctions or gets damaged and that damaged nerve fibers send the wrong signals to pain centers in your body, resulting in neuropathic pain (page 1, paragraphs 2-3). Cleveland Clinic teaches that neuropathy is a disturbance of function or a change in one or several nerves and that there are multiple diseases (diabetes, shingles, HIV/AIDS, alcohol use disorder) that can cause it (page 1, paragraph 4). Cleveland Clinic teaches that neuropathic pain is not always preventable, which implies that it is preventable in some instances (page 3, paragraph 4).
Bae (Neurotherapeutics, 2021, 18, 2384-2396) teaches that chemotherapy-induced peripheral neuropathy (CIPN) is a common and debilitating complication of several antineoplastic agents, including taxanes, platinum derivatives, vinca alkaloids, and proteasome inhibitors (page 2384, column 1, paragraph 1). Bae teaches that CIPN is sometimes mild and reversible, whereas in other cases, it can be severe and irreversible (page 2385, column 1, paragraph 2). Bae teaches that clinical risk factors for developing CIPN include a history of pre-existing neuropathy, comorbidities such as diabetes mellitus, lifestyle factors like smoking, and decreased creatinine clearance (page 2385, column 1, paragraph 3). Bae teaches small molecules, such as MDA7, capable of preventing allodynia (page 2390, column 2, paragraph 3). Bae teaches that there is currently no preventive strategy to prevent CIPN (page 2392, column 1, paragraph 2).
Predictability in the Art
Lebois teaches that there is no single disease-modifying available therapy for Alzheimer’s patients that slows or prevents the course of the disease (page 1177, column 1, paragraph 1). Lebois teaches that while many anti-amyloid therapies have shown promising effects in mouse models of Alzheimer’s, none have translated into an effective therapy in human Alzheimer’s patients (page 1177, column 1, paragraph 1). Lebois teaches that cholinergic neurotransmission is complex, whereby acetylcholine acts on multiple subtypes of both nicotinic and muscarinic acetylcholine receptors to mediate its effects (many of which functionally oppose one another) and thus it is not surprising that nonselective activators (e.g. donepezil) suffer from modest efficacy and dose-limiting side effects (page 1177, column 2, paragraph 2; page 1178, column 1, paragraph 1). Lebois teaches that the failure of all disease-modifying clinical trials to date, along with the recognition that disease pathology begins 20 or more years prior to the onset of clinical symptoms has produced a paradigm-shift in Alzheimer’s treatment efforts (page 1178, column 2, paragraph 2).
Leenaars teaches that current drug development is handicapped by high attrition rates and that many molecules that were promising during preclinical development fail during subsequent clinical testing (page 1, column 1, paragraph 1). Leenaars further teaches that animals and humans are complex systems and therefore always unpredictable (page 2, column 1, paragraph 1), which further underscores the unpredictability of the art and translation of promising chemical candidate from in vitro models to in vivo models and beyond into humans.
Mullard (Nature News & Analysis, 2020, 226) teaches that the failure of a phase II/III trial of amyloid antibodies in people with or at risk of inherited early-onset Alzheimer’s has dealt another blow to the dementia pipeline (paragraph 1). Additionally, Mullard teaches that Amgen and Novartis halted two phase III trials of the BACE1 inhibitor, umibecestat, as monotherapy and in combination with the amyloid vaccine CAD103 in high-risk patients recruited before the onset of cognitive impairment (paragraph 3).
Lowe teaches that selectively modulating muscarinic M1 receptor is not easy to attain and that the side effects will hammer you if selectivity is not achieved (page 1, paragraph 2). Lowe teaches that there is more to the mechanism of a selective M1 agonist than simple replacement (page 1, paragraph 3). Lowe teaches that there is a worry in pharma about selective M1 modulation in that without a disease-altering mechanism, then one would be boarding a sinking ship by going after cholinergic neurons (page 1, paragraph 4). Lowe teaches that donepezil inhibits acetylcholine breakdown in the synapse and does not work that well but that there is still hope from the efficacy seen with donepezil, which is mildly palliative at best and goes away after a period of treatment (page 1, paragraphs 4-5).
Welliver teaches that nonselective muscarinic receptor antagonists have been shown to improved remyelination in rodents but that current drugs have potent activity for other receptors (page 6922, column 1, paragraph 2). Welliver teaches that for success of future therapy, it is critical to determine which MR subtype or subtypes signal to block oligodendrocyte differentiation and inhibit repair (page 6922, column 1, paragraph 2). Welliver teaches that solifenacin, an M1/3R selective antagonist, induced oligodendrocyte differentiation in a mouse model of hypomyelination (page 6922, column 1, paragraph 3).
Healthline (“Is it possible to prevent multiple sclerosis,” Healthline, 2025, < healthline.com/health/multiple-sclerosis-prevention#takeaway>, accessed 14 Sept 2026) teaches that MS is a disease of the central nervous system (page 2, paragraph 2). Healthline teaches that MS cannot be prevented and that certain risk factors cannot be modified but that changing diet and lifestyle may help reduce the risk of developing MS (page 7, paragraphs 1-2).
Cleveland Clinic (“Neuropathic Pain,” Cleveland Clinic, 2026, < my.clevelandclinic.org/health/diseases/15833-neuropathic-pain>, accessed 14 Sept 2026) teaches that neuropathic pain can be mild or severe and that it can be caused by central nervous system disorders (page 1, paragraph 1). Cleveland Clinic teaches that neuropathic pain can happen if the nervous system malfunctions or gets damaged and that damaged nerve fibers send the wrong signals to pain centers in your body, resulting in neuropathic pain (page 1, paragraphs 2-3). Cleveland Clinic teaches that neuropathy is a disturbance of function or a change in one or several nerves and that there are multiple diseases (diabetes, shingles, HIV/AIDS, alcohol use disorder) can cause it (page 1, paragraph 4). Cleveland Clinic teaches that neuropathic pain is not always preventable, which implies that it is preventable in some instances (page 3, paragraph 4).
Bae (Neurotherapeutics, 2021, 18, 2384-2396) teaches that chemotherapy-induced peripheral neuropathy (CIPN) is a common and debilitating complication of several antineoplastic agents, including taxanes, platinum derivatives, vinca alkaloids, and proteasome inhibitors (page 2384, column 1, paragraph 1). Bae teaches that CIPN is sometimes mild and reversible, whereas in other cases, it can be severe and irreversible (page 2385, column 1, paragraph 2). Bae teaches that clinical risk factors for developing CIPN include a history of pre-existing neuropathy, comorbidities such as diabetes mellitus, lifestyle factors like smoking, and decreased creatinine clearance (page 2385, column 1, paragraph 3), underscoring the unpredictability in the art. Bae teaches small molecules, such as MDA7, capable of preventing allodynia (page 2390, column 2, paragraph 3). Bae teaches that there is currently no preventive strategy to prevent CIPN (page 2392, column 1, paragraph 2).
Thus, Lebois, Mullard, Lowe, Welliver, and Cleveland Clinic teach that treating a neurodegenerative disorder, a demyelinating disease, and a neuropathic disease is predictable, but Leenaars, Mullard, Lowe, Healthline, and Bae teach that preventing a neurodegenerative disorder, a demyelinating disease, and a neuropathic disease is unpredictable.
Working Examples
The instant specification teaches modulating muscarinic acetylcholine M1 receptor via a crystal of
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in CHO-K1 cells ([0200]). The instant specification does not teach applying the claimed method to any neurodegenerative disorder cell lines, demyelinating disease cell lines, or neuropathic disease cell lines for in vitro testing, much less in vivo or in patient testing.
Quantity of Experimentation
The amount of experimentation required to determine which compound, which disease or disorder, in what amounts, what order, would be astronomical. A skilled artisan would be required to start with proof-of-concept and proceed through all levels of lead identification and optimization, which is invention and not development; this is undue amount of experimentation.
As such, while the specification is enabling for the non-prophylactic treating of a neurodegenerative disorder, a demyelinating disease, and a neuropathic disease in a subject, it does not reasonably provide enablement for preventing a neurodegenerative disorder, a demyelinating disease, or a neuropathic disease.
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.
3. Claims 7-19 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 7 recites a method of treating a neurodegenerative disorder in a subject via administering a therapeutically effective amount of the crystalline compound of
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. However, the specification defines “treating” to be an approach for obtaining beneficial or desired results including but not limited to therapeutic benefit and/or prophylactic benefit ([0068]). The term “desired clinical results” in claim 7 is a relative term, which renders the claim indefinite. The term “desired clinical results” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. Accordingly, it is ambiguous as to the exact scope that Applicant considers part of the claim invention and what degree of similarity would infringe.
Dependent claims 8-9 are included for depending on a rejected claim and not reciting limitations that resolve the ambiguity.
Similarly, claim 10 recites a method of treating a demyelinating disease in a subject via administering a therapeutically effective amount of the crystalline compound of
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. However, the specification defines “treating” to be an approach for obtaining beneficial or desired results including but not limited to therapeutic benefit and/or prophylactic benefit ([0068]). The term “desired clinical results” in claim 10 is a relative term, which renders the claim indefinite. The term “desired clinical results” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. Accordingly, it is ambiguous as to the exact scope that Applicant considers part of the claim invention and what degree of similarity would infringe.
Dependent claims 11-15 are included for depending on a rejected claim and not reciting limitations that resolve the ambiguity.
Similarly, claim 16 recites a method of treating a neuropathic disease in a subject via administering a therapeutically effective amount of the crystalline compound of
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. However, the specification defines “treating” to be an approach for obtaining beneficial or desired results including but not limited to therapeutic benefit and/or prophylactic benefit ([0068]). The term “desired clinical results” in claim 16 is a relative term, which renders the claim indefinite. The term “desired clinical results” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. Accordingly, it is ambiguous as to the exact scope that Applicant considers part of the claim invention and what degree of similarity would infringe.
Dependent claims 16-19 are included for depending on a rejected claim and not reciting limitations that resolve the ambiguity.
Claim Rejections – Double Patenting
4. Claims 1-6 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 12-16 and 23-26 of U.S. Patent No. 12,565,501 in view of Carlson (US 2003/0124028, published 3 Jul 2003) and Gardner (Computers and chemical Engineering, 2004, 28, 943-953).
U.S. Patent No. 12,565,501 claims the compound,
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, and pharmaceutical compositions thereof (claims 12-16 and 23-26).
Regarding claim 1, ‘501 fails to teach a crystal of
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that is characterized by an x-ray powder diffraction pattern (XRPD) with peaks at 13.4 ± 0.15° 2θ, 14.0 ± 0.15° 2θ, 15.2 ± 0.15° 2θ, 19.3 ± 0.15° 2θ, 20.0 ± 0.15° 2θ, and 21.2 ± 0.15° 2θ.
Carlson teaches well-known systems for automated high-throughput preparation and screening of salts and polymorphs of drug candidates (abstract). Carlson teaches processes that determine suitable salts and processes that discover substantially every polymorph that can form from a particular drug candidate and a system that screens for crystalline forms of drug candidates or salts thereof (abstract; [0023]). Carlson teaches crystallization and polymorph identification via crystallizing conditions in parallel for each of the plurality of members on a substrate in different solvents or solvent mixtures and that the polymorphs are produced in glass microtiter plates or other optically transmissive substrate by cooling, evaporation, precipitation by an anti-solvent, slurry, or solvent gradients of aliquots of hot solutions ([0019]). Carlson also teaches that the crystalline structures comprising the crystals and the supernatant or mother liquor are separated from each other after the recrystallization step such that the crystals reside on a substrate, typically in regions so that the crystals can be screened individually or in parallel and that a sufficient number of screening tests are performed to make a determination of the number of polymorphs and to identify the polymorphs or salts thereof that are suitable for drug formulation ([0020]). Carlson also teaches that solvents used in the high throughput screen are ethanol, water, cyclohexane, propanol, acetonitrile, dioxane, methyl ethyl ketone, ethyl acetate, isopropyl acetate, propyl acetate, toluene, and tetrahydrofuran ([0165]; [0361]). Carlson also teaches cooling the mixture ([0264]). Carlson teaches filtering the mixture and drying under vacuum (abstract; [0124]; [0132]). Carlson teaches birefringence testing of crystals to determine the crystallinity of the sample: the quantity, size, and shape of crystals ([0195]). Additionally, Carlson teaches that different salts and polymorphs have characteristics that are desirable for a drug candidate and have different physical characteristics ([0004]-[0005]). Carlson also teaches that the polymorphic state of an active pharmaceutical ingredient can change the biological profile of the drug ([0005]).
Gardner teaches a commercially available system that is a similar system to Carlson: CrystalMax™ (page 948). Gardner teaches that CrystalMax™ is a high throughput platform for selection of forms and formulations of pharmaceutical candidates and products (page 947, column 2, paragraph 3). Gardner teaches success of CrystalMax™ in determining all polymorphs (even those previously unknown, such as Form III) in the known drug, ritonavir (page 949, column 2, paragraphs 2-3). Gardner teaches that previously drug discovery only paid a limited amount of attention to the physical/chemical properties and instead relied on solubilizing agents or pH control to force the compound into animal models or pharmacokinetic studies (page 944, column 2, paragraph 2). Gardner additionally teaches that that the consequences of ignoring these characteristics as lead candidates fall by the way-side due to the inability to administer them at appropriate doses in toxicology studies and in humans (page 945, column 1, paragraph 1). Additionally, Gardner teaches that the comprehensive investigation of the options for physical forms of drug candidates has two significant benefits: optimization of performance (e.g. oral bioavailability, suitable intravenous formulation, maximum chemical stability) and avoiding the risk of developing a metastable form which could later convert to a more stable form with physical properties that adversely affect the pharmaceutical performance of the formulation of the drug (page 945, column 2, paragraph 4).
Given the high level of skill in the art as evidenced by Carlson and Gardner, one of ordinary skill in the art would have considered the application of Carlson’s technique using a commercially available system as taught by Gardner to generate the polymorph of
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having the XRPD of 13.4 ± 0.15° 2θ, 14.0 ± 0.15° 2θ, 15.2 ± 0.15° 2θ, 19.3 ± 0.15° 2θ, 20.0 ± 0.15° 2θ, and 21.2 ± 0.15° 2θ as “routine experimentation,” because it was well-known, commercially available, and was a routine part of drug discovery as taught by Gardner (page 944, Figures 2; page 945, Figure 3).
One of ordinary skill in the art would have had a reasonable expectation of success in producing a polymorph of
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, because ‘501 teaches
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and Carlson teaches the same process using ethanol, water, cyclohexane, propanol, acetonitrile, dioxane, methyl ethyl ketone, ethyl acetate, isopropyl acetate, propyl acetate, toluene, and tetrahydrofuran, varying temperature, and filtering the crystals ([0165]; [0361]; [0264]; [0124] [0132]). “When there is a design need or market pressure to solve a problem and there are a finite number of identified, predictable solutions, a person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense. In that instance the fact that a combination was obvious to try might show that it was obvious under § 103.” KSR International Co. v Teleflex Inc., 550 U.S. 380 82 USPQ2d 1385 (2007). One of ordinary skill in the art would have known about the need to select the optimal form of the drug identified in ‘501, including the specific polymorphic forms which were known to be predictably discoverable by application of Carlson’s technique and were also within one of ordinary skill in the art’s technical grasp as evidenced by the commercially available system taught by Gardner. Thus, it would have been obvious to try and one or ordinary skill in the art would have anticipated success in the endeavor.
At the time of invention, there was an art recognized need to identify the optimal solid forms of a pharmaceutical. Carlson teaches that different salts and polymorphs have characteristics that are desirable for a drug candidate and have different physical characteristics ([0004]-[0005]). Carlson also teaches that the polymorphic state of an active pharmaceutical ingredient can change the biological profile of the drug ([0005]). Gardner teaches that previously drug discovery only paid a limited amount of attention to the physical/chemical properties and instead relied on solubilizing agents or pH control to force the compound into animal models or pharmacokinetic studies (page 944, column 2, paragraph 2). Gardner additionally teaches that that the consequences of ignoring these characteristics as lead candidates fall by the way-side due to inability to administer them at appropriate doses in toxicology studies and in humans (page 945, column 1, paragraph 1). Additionally, Gardner teaches that comprehensive investigation of the options for physical forms of drug candidates has two significant benefits: optimization of performance (e.g. oral bioavailability, suitable intravenous formulation, maximum chemical stability) and avoiding the risk of developing a metastable form which could later convert to a more stable form with physical properties that adversely affect the pharmaceutical performance of the formulation of the drug (page 945, column 2, paragraph 4). Accordingly, one of ordinary skill in the art would have pursued the commercially available system with a reasonable expectation of success, because the systems were known to identify substantially every polymorph (Carlson: abstract) and further Gardner demonstrated success with a commercial system (page 949, column 2, paragraphs 2-3). Similarly, one of ordinary skill in the art would have applied the known technique of pharmaceutical solid form optimization as taught by Carlson and Gardner to the known compound of ‘501:
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, which would have yielded the predictable result of the optimal pharmaceutical solid form. Alternatively, one of ordinary skill in the art would have used the known technique that successfully identified the optimal form of other pharmaceuticals demonstrated by Gardner and the polymorphic forms of ritonavir and applied the known optimization technique in the same way to the compound of ‘501 where the result would have been predictable due to the explicit teaching of Carlson that the technique was known to identify ‘substantially every polymorph’ and ‘suitable salt.’ Moreover, products of identical chemical composition cannot have mutually exclusive properties. In re Spada, 911 F.2d 705, 709 15 USPQ2d 1655m, 1658 (Fed. Cir. 1990). A compound composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties Applicant discloses and/or claims are necessarily present. See MPEP 2112.01 (I) -(II).
As such, an artisan having ordinary skill in the art would have been motivated to make such a selection to predictably arrive at a crystalline form of
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having the XRPD of 13.4 ± 0.15° 2θ, 14.0 ± 0.15° 2θ, 15.2 ± 0.15° 2θ, 19.3 ± 0.15° 2θ, 20.0 ± 0.15° 2θ, and 21.2 ± 0.15° 2θ.
Regarding claim 2, ‘501 claims
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and pharmaceutical compositions thereof (claims 12-16 and 23-26). Carlson teaches a method of generating a polymorph via the same process using ethanol, water, cyclohexane, propanol, acetonitrile, dioxane, methyl ethyl ketone, ethyl acetate, isopropyl acetate, propyl acetate, toluene, and tetrahydrofuran, varying temperature, and filtering the crystals ([0165]; [0361]; [0264]; [0124] [0132]), and Gardner teaches using a commercially available system to access all polymorphs of a known drug (page 947, column 2, paragraph 3; page 949, column 2, paragraphs 2-3). Accordingly, the combination of ‘501, Carlson, and Gardner teaches the crystalline compound of
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having the XRPD of 6.7 ± 0.15° 2θ, 13.4 ± 0.15° 2θ, 14.0 ± 0.15° 2θ, 15.2 ± 0.15° 2θ, 17.7 ± 0.15° 2θ, 18.1 ± 0.15° 2θ, 18.8 ± 0.15° 2θ, 19.3 ± 0.15° 2θ, 19.8 ± 0.15° 2θ, 20.0 ± 0.15° 2θ, 21.0 ± 0.15° 2θ, 21.2 ± 0.15° 2θ, and 24.1 ± 0.15° 2θ.
Regarding claim 3, ‘501 claims
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and pharmaceutical compositions thereof (claims 12-16 and 23-26). Carlson teaches a method of generating a polymorph via the same process using ethanol, water, cyclohexane, propanol, acetonitrile, dioxane, methyl ethyl ketone, ethyl acetate, isopropyl acetate, propyl acetate, toluene, and tetrahydrofuran, varying temperature, and filtering the crystals ([0165]; [0361]; [0264]; [0124] [0132]), and Gardner teaches using a commercially available system to access all polymorphs of a known drug (page 947, column 2, paragraph 3; page 949, column 2, paragraphs 2-3). Accordingly, the combination of ‘501, Carlson, and Gardner teaches the crystalline compound of
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having the XRPD of 6.7 ± 0.15° 2θ, 10.7 ± 0.15° 2θ, 13.4 ± 0.15° 2θ, 14.0 ± 0.15° 2θ, 15.2 ± 0.15° 2θ, 17.7 ± 0.15° 2θ, 18.1 ± 0.15° 2θ, 18.8 ± 0.15° 2θ, 19.3 ± 0.15° 2θ, 19.8 ± 0.15° 2θ, 20.0 ± 0.15° 2θ, 20.7 ± 0.15° 2θ, 21.0 ± 0.15° 2θ, 21.2 ± 0.15° 2θ, 24.1 ± 0.15° 2θ, 25.9 ± 0.15° 2θ, 27.8 ± 0.15° 2θ, and 30.6 ± 0.15° 2θ.
Regarding claim 4, ‘501 claims
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and pharmaceutical compositions thereof (claims 12-16 and 23-26). Carlson teaches a method of generating a polymorph via the same process using ethanol, water, cyclohexane, propanol, acetonitrile, dioxane, methyl ethyl ketone, ethyl acetate, isopropyl acetate, propyl acetate, toluene, and tetrahydrofuran, varying temperature, and filtering the crystals ([0165]; [0361]; [0264]; [0124] [0132]), and Gardner teaches using a commercially available system to access all polymorphs of a known drug (page 947, column 2, paragraph 3; page 949, column 2, paragraphs 2-3). Accordingly, the combination of ‘501, Carlson, and Gardner teaches the crystalline compound of
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having the XRPD of 6.7 ± 0.15° 2θ, 10.7 ± 0.15° 2θ, 13.4 ± 0.15° 2θ, 14.0 ± 0.15° 2θ, 15.2 ± 0.15° 2θ, 16.6 ± 0.15° 2θ , 17.7 ± 0.15° 2θ, 18.1 ± 0.15° 2θ, 18.4 ± 0.15° 2θ, 18.8 ± 0.15° 2θ, 19.3 ± 0.15° 2θ, 19.8 ± 0.15° 2θ, 20.0 ± 0.15° 2θ, 20.7 ± 0.15° 2θ, 21.0 ± 0.15° 2θ, 21.2 ± 0.15° 2θ, 24.1 ± 0.15° 2θ, 25.9 ± 0.15° 2θ, 26.3 ± 0.15° 2θ, 27.0 ± 0.15° 2θ, 27.8 ± 0.15° 2θ, and 30.6 ± 0.15° 2θ.
Regarding claim 5, ‘501 claims
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and pharmaceutical compositions thereof (claims 12-16 and 23-26). Carlson teaches a method of generating a polymorph via the same process using ethanol, water, cyclohexane, propanol, acetonitrile, dioxane, methyl ethyl ketone, ethyl acetate, isopropyl acetate, propyl acetate, toluene, and tetrahydrofuran, varying temperature, and filtering the crystals ([0165]; [0361]; [0264]; [0124] [0132]), and Gardner teaches using a commercially available system to access all polymorphs of a known drug (page 947, column 2, paragraph 3; page 949, column 2, paragraphs 2-3). Accordingly, the combination of ‘501, Carlson, and Gardner teaches the crystalline compound of
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having a differential scanning calorimetry endotherm onset at about 117 °C.
Regarding claim 6, ‘501 claims
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and pharmaceutical compositions thereof with a pharmaceutically acceptable excipient (claims 12-16 and 23-26). Carlson teaches a method of generating a polymorph via the same process using ethanol, water, cyclohexane, propanol, acetonitrile, dioxane, methyl ethyl ketone, ethyl acetate, isopropyl acetate, propyl acetate, toluene, and tetrahydrofuran, varying temperature, and filtering the crystals ([0165]; [0361]; [0264]; [0124] [0132]), and Gardner teaches using a commercially available system to access all polymorphs of a known drug (page 947, column 2, paragraph 3; page 949, column 2, paragraphs 2-3). Accordingly, the combination of ‘501, Carlson, and Gardner teaches a pharmaceutical composition of the crystalline compound of
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and a pharmaceutically acceptable excipient.
5. Claim 1-20 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 23-38 of copending Application No. 19/451,835 in view of Carlson (US 2003/0124028, published 3 Jul 2003) and Gardner (Computers and chemical Engineering, 2004, 28, 943-953).
This is a provisional nonstatutory double patenting rejection.
U.S. Application No. 19/451,835 claims the compound,
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, and pharmaceutical compositions thereof (claims 23-24). ‘835 claims a method of treating a neurodegenerative disorder, a demyelinating disease, and a neuropathic disease as well as modulating muscarinic acetylcholine receptor M1 activity in a subject via the compound,
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(claims 25-38).
Regarding claim 1, ‘835 fails to teach a crystal of
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that is characterized by an x-ray powder diffraction pattern (XRPD) with peaks at 13.4 ± 0.15° 2θ, 14.0 ± 0.15° 2θ, 15.2 ± 0.15° 2θ, 19.3 ± 0.15° 2θ, 20.0 ± 0.15° 2θ, and 21.2 ± 0.15° 2θ.
Carlson teaches well-known systems for automated high-throughput preparation and screening of salts and polymorphs of drug candidates (abstract). Carlson teaches processes that determine suitable salts and processes that discover substantially every polymorph that can form from a particular drug candidate and a system that screens for crystalline forms of drug candidates or salts thereof (abstract; [0023]). Carlson teaches crystallization and polymorph identification via crystallizing conditions in parallel for each of the plurality of members on a substrate in different solvents or solvent mixtures and that the polymorphs are produced in glass microtiter plates or other optically transmissive substrate by cooling, evaporation, precipitation by an anti-solvent, slurry, or solvent gradients of aliquots of hot solutions ([0019]). Carlson also teaches that the crystalline structures comprising the crystals and the supernatant or mother liquor are separated from each other after the recrystallization step such that the crystals reside on a substrate, typically in regions so that the crystals can be screened individually or in parallel and that a sufficient number of screening tests are performed to make a determination of the number of polymorphs and to identify the polymorphs or salts thereof that are suitable for drug formulation ([0020]). Carlson also teaches that solvents used in the high throughput screen are ethanol, water, cyclohexane, propanol, acetonitrile, dioxane, methyl ethyl ketone, ethyl acetate, isopropyl acetate, propyl acetate, toluene, and tetrahydrofuran ([0165]; [0361]). Carlson also teaches cooling the mixture ([0264]). Carlson teaches filtering the mixture and drying under vacuum (abstract; [0124]; [0132]). Carlson teaches birefringence testing of crystals to determine the crystallinity of the sample: the quantity, size, and shape of crystals ([0195]). Additionally, Carlson teaches that different salts and polymorphs have characteristics that are desirable for a drug candidate and have different physical characteristics ([0004]-[0005]). Carlson also teaches that the polymorphic state of an active pharmaceutical ingredient can change the biological profile of the drug ([0005]).
Gardner teaches a commercially available system that is a similar system to Carlson: CrystalMax™ (page 948). Gardner teaches that CrystalMax™ is a high throughput platform for selection of forms and formulations of pharmaceutical candidates and products (page 947, column 2, paragraph 3). Gardner teaches success of CrystalMax™ in determining all polymorphs (even those previously unknown, such as Form III) in the known drug, ritonavir (page 949, column 2, paragraphs 2-3). Gardner teaches that previously drug discovery only paid a limited amount of attention to the physical/chemical properties and instead relied on solubilizing agents or pH control to force the compound into animal models or pharmacokinetic studies (page 944, column 2, paragraph 2). Gardner additionally teaches that that the consequences of ignoring these characteristics as lead candidates fall by the way-side due to the inability to administer them at appropriate doses in toxicology studies and in humans (page 945, column 1, paragraph 1). Additionally, Gardner teaches that the comprehensive investigation of the options for physical forms of drug candidates has two significant benefits: optimization of performance (e.g. oral bioavailability, suitable intravenous formulation, maximum chemical stability) and avoiding the risk of developing a metastable form which could later convert to a more stable form with physical properties that adversely affect the pharmaceutical performance of the formulation of the drug (page 945, column 2, paragraph 4).
Given the high level of skill in the art as evidenced by Carlson and Gardner, one of ordinary skill in the art would have considered the application of Carlson’s technique using a commercially available system as taught by Gardner to generate the polymorph of
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having the XRPD of 13.4 ± 0.15° 2θ, 14.0 ± 0.15° 2θ, 15.2 ± 0.15° 2θ, 19.3 ± 0.15° 2θ, 20.0 ± 0.15° 2θ, and 21.2 ± 0.15° 2θ as “routine experimentation,” because it was well-known, commercially available, and was a routine part of drug discovery as taught by Gardner (page 944, Figures 2; page 945, Figure 3).
One of ordinary skill in the art would have had a reasonable expectation of success in producing a polymorph of
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, because ‘835 teaches
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and Carlson teaches the same process using ethanol, water, cyclohexane, propanol, acetonitrile, dioxane, methyl ethyl ketone, ethyl acetate, isopropyl acetate, propyl acetate, toluene, and tetrahydrofuran, varying temperature, and filtering the crystals ([0165]; [0361]; [0264]; [0124] [0132]). “When there is a design need or market pressure to solve a problem and there are a finite number of identified, predictable solutions, a person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense. In that instance the fact that a combination was obvious to try might show that it was obvious under § 103.” KSR International Co. v Teleflex Inc., 550 U.S. 380 82 USPQ2d 1385 (2007). One of ordinary skill in the art would have known about the need to select the optimal form of the drug identified in ‘835, including the specific polymorphic forms which were known to be predictably discoverable by application of Carlson’s technique and were also within one of ordinary skill in the art’s technical grasp as evidenced by the commercially available system taught by Gardner. Thus, it would have been obvious to try and one or ordinary skill in the art would have anticipated success in the endeavor.
At the time of invention, there was an art recognized need to identify the optimal solid forms of a pharmaceutical. Carlson teaches that different salts and polymorphs have characteristics that are desirable for a drug candidate and have different physical characteristics ([0004]-[0005]). Carlson also teaches that the polymorphic state of an active pharmaceutical ingredient can change the biological profile of the drug ([0005]). Gardner teaches that previously drug discovery only paid a limited amount of attention to the physical/chemical properties and instead relied on solubilizing agents or pH control to force the compound into animal models or pharmacokinetic studies (page 944, column 2, paragraph 2). Gardner additionally teaches that that the consequences of ignoring these characteristics as lead candidates fall by the way-side due to inability to administer them at appropriate doses in toxicology studies and in humans (page 945, column 1, paragraph 1). Additionally, Gardner teaches that comprehensive investigation of the options for physical forms of drug candidates has two significant benefits: optimization of performance (e.g. oral bioavailability, suitable intravenous formulation, maximum chemical stability) and avoiding the risk of developing a metastable form which could later convert to a more stable form with physical properties that adversely affect the pharmaceutical performance of the formulation of the drug (page 945, column 2, paragraph 4). Accordingly, one of ordinary skill in the art would have pursued the commercially available system with a reasonable expectation of success, because the systems were known to identify substantially every polymorph (Carlson: abstract) and further Gardner demonstrated success with a commercial system (page 949, column 2, paragraphs 2-3). Similarly, one of ordinary skill in the art would have applied the known technique of pharmaceutical solid form optimization as taught by Carlson and Gardner to the known compound of ‘835:
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, which would have yielded the predictable result of the optimal pharmaceutical solid form. Alternatively, one of ordinary skill in the art would have used the known technique that successfully identified the optimal form of other pharmaceuticals demonstrated by Gardner and the polymorphic forms of ritonavir and applied the known optimization technique in the same way to the compound of ‘835 where the result would have been predictable due to the explicit teaching of Carlson that the technique was known to identify ‘substantially every polymorph’ and ‘suitable salt.’ Moreover, products of identical chemical composition cannot have mutually exclusive properties. In re Spada, 911 F.2d 705, 709 15 USPQ2d 1655m, 1658 (Fed. Cir. 1990). A compound composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties Applicant discloses and/or claims are necessarily present. See MPEP 2112.01 (I) -(II).
As such, an artisan having ordinary skill in the art would have been motivated to make such a selection to predictably arrive at a crystalline form of
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having the XRPD of 13.4 ± 0.15° 2θ, 14.0 ± 0.15° 2θ, 15.2 ± 0.15° 2θ, 19.3 ± 0.15° 2θ, 20.0 ± 0.15° 2θ, and 21.2 ± 0.15° 2θ.
Regarding claim 2, ‘835 claims
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and pharmaceutical compositions thereof (claims 23-24). Carlson teaches a method of generating a polymorph via the same process using ethanol, water, cyclohexane, propanol, acetonitrile, dioxane, methyl ethyl ketone, ethyl acetate, isopropyl acetate, propyl acetate, toluene, and tetrahydrofuran, varying temperature, and filtering the crystals ([0165]; [0361]; [0264]; [0124] [0132]), and Gardner teaches using a commercially available system to access all polymorphs of a known drug (page 947, column 2, paragraph 3; page 949, column 2, paragraphs 2-3). Accordingly, the combination of ‘835, Carlson, and Gardner teaches the crystalline compound of
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having the XRPD of 6.7 ± 0.15° 2θ, 13.4 ± 0.15° 2θ, 14.0 ± 0.15° 2θ, 15.2 ± 0.15° 2θ, 17.7 ± 0.15° 2θ, 18.1 ± 0.15° 2θ, 18.8 ± 0.15° 2θ, 19.3 ± 0.15° 2θ, 19.8 ± 0.15° 2θ, 20.0 ± 0.15° 2θ, 21.0 ± 0.15° 2θ, 21.2 ± 0.15° 2θ, and 24.1 ± 0.15° 2θ.
Regarding claim 3, ‘835 claims
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and pharmaceutical compositions thereof (claims 23-24). Carlson teaches a method of generating a polymorph via the same process using ethanol, water, cyclohexane, propanol, acetonitrile, dioxane, methyl ethyl ketone, ethyl acetate, isopropyl acetate, propyl acetate, toluene, and tetrahydrofuran, varying temperature, and filtering the crystals ([0165]; [0361]; [0264]; [0124] [0132]), and Gardner teaches using a commercially available system to access all polymorphs of a known drug (page 947, column 2, paragraph 3; page 949, column 2, paragraphs 2-3). Accordingly, the combination of ‘835, Carlson, and Gardner teaches the crystalline compound of
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having the XRPD of 6.7 ± 0.15° 2θ, 10.7 ± 0.15° 2θ, 13.4 ± 0.15° 2θ, 14.0 ± 0.15° 2θ, 15.2 ± 0.15° 2θ, 17.7 ± 0.15° 2θ, 18.1 ± 0.15° 2θ, 18.8 ± 0.15° 2θ, 19.3 ± 0.15° 2θ, 19.8 ± 0.15° 2θ, 20.0 ± 0.15° 2θ, 20.7 ± 0.15° 2θ, 21.0 ± 0.15° 2θ, 21.2 ± 0.15° 2θ, 24.1 ± 0.15° 2θ, 25.9 ± 0.15° 2θ, 27.8 ± 0.15° 2θ, and 30.6 ± 0.15° 2θ.
Regarding claim 4, ‘835 claims
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and pharmaceutical compositions thereof (claims 23-24). Carlson teaches a method of generating a polymorph via the same process using ethanol, water, cyclohexane, propanol, acetonitrile, dioxane, methyl ethyl ketone, ethyl acetate, isopropyl acetate, propyl acetate, toluene, and tetrahydrofuran, varying temperature, and filtering the crystals ([0165]; [0361]; [0264]; [0124] [0132]), and Gardner teaches using a commercially available system to access all polymorphs of a known drug (page 947, column 2, paragraph 3; page 949, column 2, paragraphs 2-3). Accordingly, the combination of ‘835, Carlson, and Gardner teaches the crystalline compound of
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having the XRPD of 6.7 ± 0.15° 2θ, 10.7 ± 0.15° 2θ, 13.4 ± 0.15° 2θ, 14.0 ± 0.15° 2θ, 15.2 ± 0.15° 2θ, 16.6 ± 0.15° 2θ , 17.7 ± 0.15° 2θ, 18.1 ± 0.15° 2θ, 18.4 ± 0.15° 2θ, 18.8 ± 0.15° 2θ, 19.3 ± 0.15° 2θ, 19.8 ± 0.15° 2θ, 20.0 ± 0.15° 2θ, 20.7 ± 0.15° 2θ, 21.0 ± 0.15° 2θ, 21.2 ± 0.15° 2θ, 24.1 ± 0.15° 2θ, 25.9 ± 0.15° 2θ, 26.3 ± 0.15° 2θ, 27.0 ± 0.15° 2θ, 27.8 ± 0.15° 2θ, and 30.6 ± 0.15° 2θ.
Regarding claim 5, ‘835 claims
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and pharmaceutical compositions thereof (claims 23-24). Carlson teaches a method of generating a polymorph via the same process using ethanol, water, cyclohexane, propanol, acetonitrile, dioxane, methyl ethyl ketone, ethyl acetate, isopropyl acetate, propyl acetate, toluene, and tetrahydrofuran, varying temperature, and filtering the crystals ([0165]; [0361]; [0264]; [0124] [0132]), and Gardner teaches using a commercially available system to access all polymorphs of a known drug (page 947, column 2, paragraph 3; page 949, column 2, paragraphs 2-3). Accordingly, the combination of ‘835, Carlson, and Gardner teaches the crystalline compound of
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having a differential scanning calorimetry endotherm onset at about 117 °C.
Regarding claim 6, ‘835 claims
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and pharmaceutical compositions thereof with a pharmaceutically acceptable excipient (claims 23-24). Carlson teaches a method of generating a polymorph via the same process using ethanol, water, cyclohexane, propanol, acetonitrile, dioxane, methyl ethyl ketone, ethyl acetate, isopropyl acetate, propyl acetate, toluene, and tetrahydrofuran, varying temperature, and filtering the crystals ([0165]; [0361]; [0264]; [0124] [0132]), and Gardner teaches using a commercially available system to access all polymorphs of a known drug (page 947, column 2, paragraph 3; page 949, column 2, paragraphs 2-3). Accordingly, the combination of ‘835, Carlson, and Gardner teaches a pharmaceutical composition of the crystalline compound of
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and a pharmaceutically acceptable excipient.
Regarding claim 7, ‘835 claims a method of treating a neurodegenerative disorder via a therapeutically effective amount of
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(claims 23-25). Carlson teaches a method of generating a polymorph via the same process using ethanol, water, cyclohexane, propanol, acetonitrile, dioxane, methyl ethyl ketone, ethyl acetate, isopropyl acetate, propyl acetate, toluene, and tetrahydrofuran, varying temperature, and filtering the crystals ([0165]; [0361]; [0264]; [0124] [0132]), and Gardner teaches using a commercially available system to access all polymorphs of a known drug (page 947, column 2, paragraph 3; page 949, column 2, paragraphs 2-3). Accordingly, the combination of ‘835, Carlson, and Gardner teaches a method of treating a neurodegenerative disorder via a therapeutically effective amount of a crystalline compound of
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.
Regarding claim 8, ‘835 claims the administration of one or more immunomodulatory agents (claims 23-26). Carlson teaches a method of generating a polymorph via the same process using ethanol, water, cyclohexane, propanol, acetonitrile, dioxane, methyl ethyl ketone, ethyl acetate, isopropyl acetate, propyl acetate, toluene, and tetrahydrofuran, varying temperature, and filtering the crystals ([0165]; [0361]; [0264]; [0124] [0132]), and Gardner teaches using a commercially available system to access all polymorphs of a known drug (page 947, column 2, paragraph 3; page 949, column 2, paragraphs 2-3). Accordingly, the combination of ‘835, Carlson, and Gardner teaches a method of treating a neurodegenerative disorder via a therapeutically effective amount of a crystalline compound of
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with one or more immunomodulatory agents.
Regarding claim 9, ‘835 claims one or more immunomodulatory agents selected from IFN-beta 1 molecule, a corticosteroid, a polymer of glutamic acid, lysine, alanine, tyrosine, or glatiramer, natalizumb, an anthracenedione molecule or mitoxantrone, a fingolimod or FTY720 or other S1P1 functional modulator, a dimethyl fumarate or other NRF2 functional modulator, daclizumab, alemtuzumab, ocrelizumab, or an inhibitor of a dihydroorotate dehydrogenase or teriflunomide (claims 23-27). Carlson teaches a method of generating a polymorph via the same process using ethanol, water, cyclohexane, propanol, acetonitrile, dioxane, methyl ethyl ketone, ethyl acetate, isopropyl acetate, propyl acetate, toluene, and tetrahydrofuran, varying temperature, and filtering the crystals ([0165]; [0361]; [0264]; [0124] [0132]), and Gardner teaches using a commercially available system to access all polymorphs of a known drug (page 947, column 2, paragraph 3; page 949, column 2, paragraphs 2-3). Accordingly, the combination of ‘835, Carlson, and Gardner teaches a method of treating a neurodegenerative disorder via a therapeutically effective amount of a crystalline compound of
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with one or more immunomodulatory agents selected from IFN-beta 1 molecule, a corticosteroid, a polymer of glutamic acid, lysine, alanine, tyrosine, or glatiramer, natalizumb, an anthracenedione molecule or mitoxantrone, a fingolimod or FTY720 or other S1P1 functional modulator, a dimethyl fumarate or other NRF2 functional modulator, daclizumab, alemtuzumab, ocrelizumab, or an inhibitor of a dihydroorotate dehydrogenase or teriflunomide.
Regarding claim 10, ‘835 claims a method of treating a demyelinating disease via a therapeutically effective amount of
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(claims 23-24 and 28). Carlson teaches a method of generating a polymorph via the same process using ethanol, water, cyclohexane, propanol, acetonitrile, dioxane, methyl ethyl ketone, ethyl acetate, isopropyl acetate, propyl acetate, toluene, and tetrahydrofuran, varying temperature, and filtering the crystals ([0165]; [0361]; [0264]; [0124] [0132]), and Gardner teaches using a commercially available system to access all polymorphs of a known drug (page 947, column 2, paragraph 3; page 949, column 2, paragraphs 2-3). Accordingly, the combination of ‘835, Carlson, and Gardner teaches a method of treating a demyelinating disease via a therapeutically effective amount of a crystalline compound of
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.
Regarding claim 11, ‘835 claims the demyelinating disease is of the central nervous system (claims 23-24 and 28-29). Carlson teaches a method of generating a polymorph via the same process using ethanol, water, cyclohexane, propanol, acetonitrile, dioxane, methyl ethyl ketone, ethyl acetate, isopropyl acetate, propyl acetate, toluene, and tetrahydrofuran, varying temperature, and filtering the crystals ([0165]; [0361]; [0264]; [0124] [0132]), and Gardner teaches using a commercially available system to access all polymorphs of a known drug (page 947, column 2, paragraph 3; page 949, column 2, paragraphs 2-3). Accordingly, the combination of ‘835, Carlson, and Gardner teaches a method of treating a demyelinating disease of the central nervous system via a therapeutically effective amount of a crystalline compound of
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.
Regarding claim 12, ‘835 claims the demyelinating disease is multiple sclerosis (claims 23-24 and 28-30). Carlson teaches a method of generating a polymorph via the same process using ethanol, water, cyclohexane, propanol, acetonitrile, dioxane, methyl ethyl ketone, ethyl acetate, isopropyl acetate, propyl acetate, toluene, and tetrahydrofuran, varying temperature, and filtering the crystals ([0165]; [0361]; [0264]; [0124] [0132]), and Gardner teaches using a commercially available system to access all polymorphs of a known drug (page 947, column 2, paragraph 3; page 949, column 2, paragraphs 2-3). Accordingly, the combination of ‘835, Carlson, and Gardner teaches a method of treating multiple sclerosis via a therapeutically effective amount of a crystalline compound of
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Regarding claim 13, ‘835 claims the demyelinating disease is of the peripheral nervous system (claims 23-24, 28-29, and 31). Carlson teaches a method of generating a polymorph via the same process using ethanol, water, cyclohexane, propanol, acetonitrile, dioxane, methyl ethyl ketone, ethyl acetate, isopropyl acetate, propyl acetate, toluene, and tetrahydrofuran, varying temperature, and filtering the crystals ([0165]; [0361]; [0264]; [0124] [0132]), and Gardner teaches using a commercially available system to access all polymorphs of a known drug (page 947, column 2, paragraph 3; page 949, column 2, paragraphs 2-3). Accordingly, the combination of ‘835, Carlson, and Gardner teaches a method of treating a demyelinating disease of the peripheral nervous system via a therapeutically effective amount of a crystalline compound of
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Regarding claim 14, ‘835 claims administration with one or more immunomodulatory agents (claims 23-24, 28, and 32). Carlson teaches a method of generating a polymorph via the same process using ethanol, water, cyclohexane, propanol, acetonitrile, dioxane, methyl ethyl ketone, ethyl acetate, isopropyl acetate, propyl acetate, toluene, and tetrahydrofuran, varying temperature, and filtering the crystals ([0165]; [0361]; [0264]; [0124] [0132]), and Gardner teaches using a commercially available system to access all polymorphs of a known drug (page 947, column 2, paragraph 3; page 949, column 2, paragraphs 2-3). Accordingly, the combination of ‘835, Carlson, and Gardner teaches a method of treating a demyelinating disease via a therapeutically effective amount of a crystalline compound of
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with one or more immunomodulatory agents.
Regarding claim 15, ‘835 claims one or more immunomodulatory agents selected from IFN-beta 1 molecule, a corticosteroid, a polymer of glutamic acid, lysine, alanine, tyrosine, or glatiramer, natalizumb, an anthracenedione molecule or mitoxantrone, a fingolimod or FTY720 or other S1P1 functional modulator, a dimethyl fumarate or other NRF2 functional modulator, daclizumab, alemtuzumab, ocrelizumab, or an inhibitor of a dihydroorotate dehydrogenase or teriflunomide (claims 23-24, 28, and 32-33). Carlson teaches a method of generating a polymorph via the same process using ethanol, water, cyclohexane, propanol, acetonitrile, dioxane, methyl ethyl ketone, ethyl acetate, isopropyl acetate, propyl acetate, toluene, and tetrahydrofuran, varying temperature, and filtering the crystals ([0165]; [0361]; [0264]; [0124] [0132]), and Gardner teaches using a commercially available system to access all polymorphs of a known drug (page 947, column 2, paragraph 3; page 949, column 2, paragraphs 2-3). Accordingly, the combination of ‘835, Carlson, and Gardner teaches a method of treating a demyelinating disease via a therapeutically effective amount of a crystalline compound of
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with one or more immunomodulatory agents selected from IFN-beta 1 molecule, a corticosteroid, a polymer of glutamic acid, lysine, alanine, tyrosine, or glatiramer, natalizumb, an anthracenedione molecule or mitoxantrone, a fingolimod or FTY720 or other S1P1 functional modulator, a dimethyl fumarate or other NRF2 functional modulator, daclizumab, alemtuzumab, ocrelizumab, or an inhibitor of a dihydroorotate dehydrogenase or teriflunomide.
Regarding claim 16, ‘835 claims a method of treating a demyelinating disease via a therapeutically effective amount of
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(claims 23-24 and 34). Carlson teaches a method of generating a polymorph via the same process using ethanol, water, cyclohexane, propanol, acetonitrile, dioxane, methyl ethyl ketone, ethyl acetate, isopropyl acetate, propyl acetate, toluene, and tetrahydrofuran, varying temperature, and filtering the crystals ([0165]; [0361]; [0264]; [0124] [0132]), and Gardner teaches using a commercially available system to access all polymorphs of a known drug (page 947, column 2, paragraph 3; page 949, column 2, paragraphs 2-3). Accordingly, the combination of ‘835, Carlson, and Gardner teaches a method of treating a neuropathic disease via a therapeutically effective amount of a crystalline compound of
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.
Regarding claim 17, ‘835 claims the neuropathic disease is diabetic neuropathy (claims 23-24 and 34-35). Carlson teaches a method of generating a polymorph via the same process using ethanol, water, cyclohexane, propanol, acetonitrile, dioxane, methyl ethyl ketone, ethyl acetate, isopropyl acetate, propyl acetate, toluene, and tetrahydrofuran, varying temperature, and filtering the crystals ([0165]; [0361]; [0264]; [0124] [0132]), and Gardner teaches using a commercially available system to access all polymorphs of a known drug (page 947, column 2, paragraph 3; page 949, column 2, paragraphs 2-3). Accordingly, the combination of ‘835, Carlson, and Gardner teaches a method of treating a diabetic neuropathy via a therapeutically effective amount of a crystalline compound of
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.
Regarding claim 18, ‘835 claims administering with one or more immunomodulatory agents (claims 23-24, 34, and 36). Carlson teaches a method of generating a polymorph via the same process using ethanol, water, cyclohexane, propanol, acetonitrile, dioxane, methyl ethyl ketone, ethyl acetate, isopropyl acetate, propyl acetate, toluene, and tetrahydrofuran, varying temperature, and filtering the crystals ([0165]; [0361]; [0264]; [0124] [0132]), and Gardner teaches using a commercially available system to access all polymorphs of a known drug (page 947, column 2, paragraph 3; page 949, column 2, paragraphs 2-3). Accordingly, the combination of ‘835, Carlson, and Gardner teaches a method of treating a neuropathic disease via a therapeutically effective amount of a crystalline compound of
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with one or more immunomodulatory agents.
Regarding claim 19, ‘835 claims one or more immunomodulatory agents selected from IFN-beta 1 molecule, a corticosteroid, a polymer of glutamic acid, lysine, alanine, tyrosine, or glatiramer, natalizumb, an anthracenedione molecule or mitoxantrone, a fingolimod or FTY720 or other S1P1 functional modulator, a dimethyl fumarate or other NRF2 functional modulator, daclizumab, alemtuzumab, ocrelizumab, or an inhibitor of a dihydroorotate dehydrogenase or teriflunomide (claims 23-24, 34, and 36-37). Carlson teaches a method of generating a polymorph via the same process using ethanol, water, cyclohexane, propanol, acetonitrile, dioxane, methyl ethyl ketone, ethyl acetate, isopropyl acetate, propyl acetate, toluene, and tetrahydrofuran, varying temperature, and filtering the crystals ([0165]; [0361]; [0264]; [0124] [0132]), and Gardner teaches using a commercially available system to access all polymorphs of a known drug (page 947, column 2, paragraph 3; page 949, column 2, paragraphs 2-3). Accordingly, the combination of ‘835, Carlson, and Gardner teaches a method of treating a neuropathic disease via a therapeutically effective amount of a crystalline compound of
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with one or more immunomodulatory agents selected from IFN-beta 1 molecule, a corticosteroid, a polymer of glutamic acid, lysine, alanine, tyrosine, or glatiramer, natalizumb, an anthracenedione molecule or mitoxantrone, a fingolimod or FTY720 or other S1P1 functional modulator, a dimethyl fumarate or other NRF2 functional modulator, daclizumab, alemtuzumab, ocrelizumab, or an inhibitor of a dihydroorotate dehydrogenase or teriflunomide.
Regarding claim 20, ‘835 claims a method of modulating muscarinic acetylcholine receptor M1 activity via a therapeutically effective amount of
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(claims 23-24 and 38). Carlson teaches a method of generating a polymorph via the same process using ethanol, water, cyclohexane, propanol, acetonitrile, dioxane, methyl ethyl ketone, ethyl acetate, isopropyl acetate, propyl acetate, toluene, and tetrahydrofuran, varying temperature, and filtering the crystals ([0165]; [0361]; [0264]; [0124] [0132]), and Gardner teaches using a commercially available system to access all polymorphs of a known drug (page 947, column 2, paragraph 3; page 949, column 2, paragraphs 2-3). Accordingly, the combination of ‘835, Carlson, and Gardner teaches a method of modulating muscarinic acetylcholine receptor M1 activity in a subject via a therapeutically effective amount of a crystalline compound of
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.
Relevant Art
The prior art made of record and not relied upon is considered pertinent to Applicant’s disclosure. The reference, Morissette (Adv. Drug Delivery Rev.¸2004, 56, 275-300), is close prior art that teaches a high throughput method of generating polymorphs (crystals) of active pharmaceutical ingredients (abstract). Additionally, Morissette teaches that pharmaceutical companies currently use high throughput screening of polymorphs to save time and reduce costs (page 288, column 1, paragraph 1). Thus, Morissette teaches that high throughput screening produces many polymorphs in a short period of time.
Conclusion
No claim is allowed.
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/MADELINE M. DEKARSKE/Examiner, Art Unit 1622
/JAMES H ALSTRUM-ACEVEDO/Supervisory Patent Examiner, Art Unit 1622
