DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Formal Matters
Applicant’s claim amendments and arguments in reply filed on 03 November 2025 are acknowledged and have been fully considered. Claims 51-80 are pending. Claims 51-63 are under consideration in the instant office action. Claims 64-80 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention and/or species, there being no allowable generic or linking claim. Claims 1-50 are canceled. Applicant’s claim amendments and arguments did not overcome the rejections under 35 USC 103 set forth in the previous office action for reasons set forth in the previous office action and herein below.
Response to the reply of the Advisory Note
Regarding the wrong claim sets Applicant indicated that “Applicant mistakenly labeled each copy with the Document Code “CLM”. Instead, each of copy should have been labeled with the Document Code “NPL”, for Non-Patent Literature (MPEP 609.04(a)(I)). Today, Applicant’s representative had a telephone call with a representative of the Patent Office’s Electronic Business Center (“EBC”). The EBC representative kindly advised Applicant’s representative that the Patent Office will change the Document Codes for each claim set submitted with the July 8, 2025 IDS from “CLM” to “NPL”. The EBC representative informed Applicant’s representative that the matter regarding the document code changes for the subject application has been assigned Reference No. 2-00624997.”
The examiner thanks Applicant for the effort to correct the document code and the examiner will continue to monitor the anticipated corrections.
Withdrawn Objections/Rejections
Rejections and/or objections not reiterated from previous office actions are hereby withdrawn as are those rejections and/or objections expressly stated to be withdrawn.
Rejections Maintained
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 51-63 remain rejected under 35 U.S.C. 103 as being unpatentable over Ziegler (US20060084656, IDS reference) in view of McCulloch et al. (Journal of Physiology, 516.2, pp. 471-484, 1999), Akerman et al. (British Journal of Pharmacology, 2003, 140(4), 718-724), and Rollema et al. (Neurochemistry International 58 (2011) 78–84).
Applicant Claims
Applicant claims a method of activating a trigeminal nerve in human by administering varenicline.
Determination of the Scope and Content of the Prior Art (MPEP §2141.01)
Ziegler teaches varenicline binds to neuronal nicotinic acetylcholine specific receptor (nAChRs) sites and is useful in modulating cholinergic function. Accordingly, this compound is useful in the treatment of various conditions or diseases including, but not limited to, inflammatory bowel disease (including, but not limited to, ulcerative colitis, pyoderma gangrenosum and Crohn's disease), irritable bowel syndrome, spastic dystonia, chronic pain, acute pain, celiac sprue, pouchitis, vasoconstriction, anxiety, panic disorder, depression, bipolar disorder, autism, sleep disorders, jet lag, amyotrophic lateral sclerosis (ALS), cognitive dysfunction, hypertension, bulimia, anorexia, obesity, cardiac arrhythmias, gastric acid hypersecretion, ulcers, pheochromocytoma, progressive supranuclear palsy, chemical dependencies and addictions (e.g., dependencies on, or addictions to nicotine (and/or tobacco products), alcohol, benzodiazepines, barbiturates, opioids or cocaine), headache, migraine, stroke, traumatic brain injury (TBI), obsessive-compulsive disorder (OCD), psychosis, Huntington's chorea, tardive dyskinesia, hyperkinesia, dyslexia, schizophrenia, multi-infarct dementia, age-related cognitive decline, epilepsy, including petit mal absence epilepsy, senile dementia of the Alzheimer's type (AD), Parkinson's disease (PD), attention deficit hyperactivity disorder (ADHD) and Tourette's Syndrome (paragraph 0006). Ziegler teaches a composition for nasal administration comprising varenicline or its pharmaceutically acceptable salt and at least one excipient. The invention also provides a composition for buccal administration comprising varenicline or its pharmaceutically acceptable salt and at least one excipient to form a solid dosage form, wherein the solid dosage form disintegrates in an oral cavity at body temperature and may adhere to body tissue of the oral cavity; a composition for pulmonary administration comprising varenicline or its pharmaceutically acceptable salt and at least one excipient; and, a method for reducing nicotine addiction, aiding in the cessation of, or lessening of tobacco use in a subject (see abstract). The present invention has numerous embodiments. In any of the embodiments, pharmaceutical compositions of varenicline can be desirably administered in doses ranging from about 0.1 mgA up to about 6 mgA per day (where mgA refers to mg of active drug based on the free base form of the drug), more preferably from about 0.5 to 4 mgA/day, and most preferably from about 1 to 4 mgA per day in single or divided doses. Variations in such dosages, however, necessarily occur depending upon the weight and condition of the subject being treated. Depending on individual responses, dosage levels below the lower limit of the aforesaid range can be more than adequate, while in other cases still larger doses can be employed without causing any harmful side effects. The final pharmaceutical composition is processed into a unit dosage form and then packaged for distribution. The processing step varies depending upon the particular unit dosage form. For example, a tablet is generally compressed under pressure into a desired shape. Those of skill in the art are well aware of the procedures used for manufacturing the various unit dosage forms (paragraph 0030). A nasal spray solution is exemplified herein. Varenicline tartrate (1.5 g) is dissolved in 100 ml 0.05M Phosphate buffer (pH 4.4) and sufficient sodium chloride is added to the solution to make it isotonic. The solution is placed in a nasal administrator designed to deliver 100 μl of spray for each application. One spray in each nostril delivers a total of 3 mg of varenicline tartrate (approximately equivalent to 1.7 mg varenicline free base) (paragraph 0070, example 3). The total dosage amount is about 100 micrograms to about 6 mg, with a dose of 1.7 mg exemplified for intranasal administration (paragraphs 0030 and 0070). One can calculate an overall concentration of 1.7 mg varenicline free base per 100 μl of spray solution which is equivalent to 1.7 mg/0.1 ml which overlaps in scope with claimed concentrations. The intranasal administration is with one spray per nostril, i.e., delivered in alternating nostrils (paragraph 70). Thus, dose per spray (i.e., per nostril) would be about 50 micrograms to about 3 mg, with 865 micrograms exemplified. These ranges render obvious the claimed ranges. The intranasal compositions may also contain one or more preservatives selected from quaternary ammonium salts such as lauralkonium chloride, benzalkonium chloride etc. (paragraph 0045), the examiner notes that “may” entails the preservatives are optional with the broadest reasonable interpretation). Furthermore the examples such as example 3 do not contain a preservative in Ziegler et al.).
Ascertainment of the Difference Between Scope of the Prior Art and the Claims
(MPEP §2141.012)
Ziegler does not teach a method of activating a trigeminal nerve in human by administering varenicline. This deficiency is cured by the teachings of McCulloch et al. and Akerman et al.
McCulloch et al. teach chemical stimulation of the nasal mucosa in rats activates trigeminal nerve afferents, leading to physiological responses such as increased cerebral blood flow and systematic blood pressure via rostral ventolateral medulla (abstract and see page 471). This study uses ammonia vapor as a chemical stimulant but demonstrates that trigeminal nerve ending in the nasal mucosa which express receptors including nAChRs are responsive to chemical agents (page 472). The examiner notes that McCulloch et al.’s teaching establishes that the trigeminal nerve can be activated pharmacologically through nasal administration providing pathway which is a relevant teachings to varenicline.
Akerman et al. teach chemical stimulation of trigeminal sensory nerve fibers using capsaicin which induces physiological responses such as dural vasodilation via calcitonin gene related peptide release (abstract and page 718). While capsaicin targets TRPV1 receptors the study confirms that trigeminal nerve endings are amenable to chemical activation including in the nasal mucosa which is innervated by trigeminal branches (page 720). These teachings by Akerman also support the general principle of pharmacologically targeting trigeminal nerve receptors for therapeutic effects.
Although Ziegler teach a nasal spray solution is exemplified herein. Varenicline tartrate (1.5 g) is dissolved in 100 ml 0.05M Phosphate buffer (pH 4.4) and sufficient sodium chloride is added to the solution to make it isotonic. The solution is placed in a nasal administrator designed to deliver 100 μl of spray for each application. One spray in each nostril delivers a total of 3 mg of varenicline tartrate (approximately equivalent to 1.7 mg varenicline free base) (paragraph 0070, example 3). The total dosage amount is about 100 micrograms to about 6 mg, with a dose of 1.7 mg exemplified for intranasal administration (Ziegler, paragraphs 30 and 70). One can calculate an overall concentration of 1.7 mg varenicline free base per 100 μl of spray solution which is equivalent to 1.7 mg/0.1 ml, Ziegler, McCulloch et al., and Akerman do not specifically exemplify the concentration of varenicline between about 0.1mg/ml and about 10 mg/ml. This deficiency is cured by the teachings of Rollema et al.
Rollema et al. teach in view of the high comorbidity of nicotine dependence with mood disorders, this study investigated potential interactions of the smoking cessation agent varenicline with two antidepressant drugs, an SSRI (sertraline) and an MAOI (clorgyline), in a preclinical animal model (see conclusion). Rollema et al. teach that at least four pre-drug basal samples were collected before compounds were administered (varenicline, 1 mg/ml free-base in saline; clorgyline, 4 mg/ml free-base in saline; sertraline 17.8 mg/ml free-base in 20% solutol; all compounds and vehicles were administered s.c. in a volume of 1 ml/kg s.c.). Effects of each compound alone on monoamine dialysate levels were determined by administering varenicline, sertraline, clorgyline or corresponding vehicles and collecting 15-min samples for 4.5 h (see materials and methods section).
Finding of Prima Facie Obviousness Rationale and Motivation
(MPEP §2142-2143)
It would have been prima facie obvious before the effective filing date of the instant application to modify the teachings of Zigler et al. for a method of activating a trigeminal nerve in human by administering varenicline free base because McCulloch et al. teach chemical stimulation of the nasal mucosa in rats activates trigeminal nerve afferents, leading to physiological responses such as increased cerebral blood flow and systematic blood pressure via rostral ventolateral medulla (abstract and see page 471). This study use ammonia vapor as a chemical stimulant but demonstrates that trigeminal nerve ending in the nasal mucosa which express receptors including nAChRs are responsive to chemical agents (page 472). Similarly, Akerman et al. teach chemical stimulation of trigeminal sensory nerve fibers using capsaicin which induces physiological responses such as dural vasodilation via calcitonin gene related peptide release (abstract and page 718). While capsaicin targets TRPV1 receptors the study confirms that trigeminal nerve endings are amenable to chemical activation including in the nasal mucosa which is innervated by trigeminal branches (page 720). These teachings by Akerman also support the general principle of pharmacologically targeting trigeminal nerve receptors for therapeutic effects. One of ordinary skill in the art would have been motivated to do so because first Zigler clearly teach that Varenicline binds to neuronal nicotinic acetylcholine specific receptor (nAChRs) sites and is useful in modulating cholinergic function. McCulloch et al teach that nAChRs are expressed on trigeminal nerve endings, including the nasal mucosa (page 472). One of ordinary skill in the art would recognize that vareniclines action on nAChRs could extend to peripheral sites like the trigeminal nerve given its pharmacological profile. One of ordinary skill in the art, aware of varenicline’s nAChRs agonism based on Zigler and the trigeminal nerve’s responsiveness to chemical stimulation via nasal administration as McCulloch et al. would have been motivated to administer varenicline to activate trigeminal nAChRs expecting physiological effects similar to those observed with other stimulants described by McCulloch et al. and Akerman et al. The nasal mucosa’s accessibility and trigerminal innervation provide a clear delivery route as validated by Zigler’s nasal spray. The combination of the references renders the instant invention obvious as it involves applying a known compound varenicline to a known target trigeminal nAChRs for a predictable outcome which is nerve activation. Furthermore, in the case where the claimed ranges for the amounts and concentrations of active agent and other ingredients “overlap or lie inside ranges disclosed by the prior art” a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). Similarly, a prima facie case of obviousness exists where the claimed ranges and prior art ranges do not overlap but are close enough that one skilled in the art would have expected them to have the same properties. Titanium Metals Corp. of America v. Banner, 778 F.2d 775, 227 USPQ 773 (Fed. Cir. 1985). Furthermore, generally differences in concentration will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. “[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). It is within the purview of the skilled artisan to optimize the amounts of active agents and ingredients. The skilled artisan would have had a reasonable expectation of success in combining the teachings of Ziegler, McColloch, and Akerman because all of the references teach targeting nicotinic acetylcholine receptor (nAChRs).
It would have been prima facie obvious before the effective filing date of the instant application to modify the teachings of Ziegler, McCulloch et al., and Akerman by utilizing varenicline in concentration of about 0.1mg/ml and about 10 mg/ml. because Rollema et al. teach that in view of the high comorbidity of nicotine dependence with mood disorders, this study investigated potential interactions of the smoking cessation agent varenicline with two antidepressant drugs, an SSRI (sertraline) and an MAOI (clorgyline), in a preclinical animal model (see conclusion). One of ordinary skill in the art would have been motivated to do so because Rollema et al. demonstrates the effective utilization of for instance 1 mg/ml concentration for varenicline. Rollema et al. teach that at least four pre-drug basal samples were collected before compounds were administered (varenicline, 1 mg/ml free-base in saline; clorgyline, 4 mg/ml free-base in saline; sertraline 17.8 mg/ml free-base in 20% solutol; all compounds and vehicles were administered s.c. in a volume of 1 ml/kg s.c.). Effects of each compound alone on monoamine dialysate levels were determined by administering varenicline, sertraline, clorgyline or corresponding vehicles and collecting 15-min samples for 4.5 h (see materials and methods section). The rationale to support a conclusion that the claim would have been obvious is that all the claimed elements were known in the prior art and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions, and the combination yielded nothing more than predictable results to one of ordinary skill in the art. KSR, 550 U.S. at 416, 82 USPQ2d at 1395; B/E Aerospace, Inc. v. C&D Zodiac, Inc., 962 F.3d 1373, 1379, 2020 USPQ2d 10706 (Fed. Cir. 2020); Sakraida v. AG Pro, Inc., 425 U.S. 273, 282, 189 USPQ 449, 453 (1976); Anderson’s-Black Rock, Inc. v. Pavement Salvage Co., 396 U.S. 57, 62-63, 163 USPQ 673, 675 (1969); Great Atl. & P. Tea Co. v. Supermarket Equip. Corp., 340 U.S. 147, 152, 87 USPQ 303, 306 (1950). Furthermore, in the case where the claimed ranges for the amounts and concentrations of active agent and other ingredients “overlap or lie inside ranges disclosed by the prior art” a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). Similarly, a prima facie case of obviousness exists where the claimed ranges and prior art ranges do not overlap but are close enough that one skilled in the art would have expected them to have the same properties. Titanium Metals Corp. of America v. Banner, 778 F.2d 775, 227 USPQ 773 (Fed. Cir. 1985). Furthermore, generally differences in concentration will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. “[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). It is within the purview of the skilled artisan to optimize the amounts of active agents and ingredients. The skilled artisan would have had a reasonable expectation of success in combining the teachings of Ziegler, McColloch, Akerman, and Rollema et al. because all of the references teach targeting nicotinic acetylcholine receptor (nAChRs).
In light of the forgoing discussion, the Examiner concludes that the subject matter defined by the instant claims would have been obvious within the meaning of 35 USC 103. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant invention, as evidenced by the references, especially in the absence of evidence to the contrary.
Response to Arguments
Applicant argues that to expedite prosecution, Applicant submits the following experimental data in support of the unexpected finding that not all nicotinic acetylcholine receptor (nAChR) agonists exhibit the same tearing effect, and that varenicline, relative to certain other nAChR agonists, has a particular pharmacological effect making it beneficial for treating conditions such as dry eye. (The undersigned notes that the following data was also submitted on August 3, 2016, in a Declaration pursuant to 37 C.F.R. 1.132 (the “Ackermann Declaration”) in connection with U.S. Patent Application 14/887,259, now U.S. Patent 9,504,645, which is related to the present application by a common priority claim): A panel of twenty compounds, including eight nAChR agonists, with various receptor binding profiles were tested. At the onset of the experiment, 50 microliters of a 0.01 mg/mL compound formulation was administered intranasally to three subjects. The dose of each compound was increased logarithmically until an effect on tearing and/or a discomfort response was observed, up to a maximum compound concentration of 10 mg/mL. The effect on tearing and the discomfort response were recorded for each compound (Table 1).
The above assertions are not found persuasive because first the examiner reminds Applicant that the current claims are drawn to a method of activating a trigeminal nerve in a human in need thereof comprising administering a therapeutically effective amount of varenicline to the human. The experimental data described in table 1 of Applicant’s response to determine the effect on tearing and/or discomfort response. It is unclear how such data can be applicable to a method of activating a trigeminal nerve in a human in need thereof comprising administering a therapeutically effective amount of varenicline to the human. Applicant provided no explanation to the claimed method. It should be noticed that Applicant is not claiming a composition of matter. There must be a nexus between the surprising results and the claimed method. Furthermore, arguendo there is a surprising result any differences between the claimed invention and the prior art may be expected to result in some differences in properties. The issue is whether the properties differ to such an extent that the difference is really unexpected. In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986) (differences in sedative and anticholinergic effects between prior art and claimed antidepressants were not unexpected). In In re Waymouth, 499 F.2d 1273, 1276, 182 USPQ 290, 293 (CCPA 1974). The evidence relied upon should establish "that the differences in results are in fact unexpected and unobvious and of both statistical and practical significance." Ex parte Gelles, 22 USPQ2d 1318, 1319 (Bd. Pat. App. & Inter. 1992). The examiner also reminds Applicant that Whether the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the "objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support." In other words, the showing of unexpected results must be reviewed to see if the results occur over the entire claimed range. In re Clemens, 622 F.2d 1029, 1036, 206 USPQ 289, 296 (CCPA 1980) (Claims were directed to a process for removing corrosion at "elevated temperatures" using a certain ion exchange resin (with the exception of claim 8 which recited a temperature in excess of 100°C). Appellant demonstrated unexpected results via comparative tests with the prior art ion exchange resin at 110°C and 130°C. The court affirmed the rejection of claims 1-7 and 9-10 because the term "elevated temperatures" encompassed temperatures as low as 60°C where the prior art ion exchange resin was known to perform well. The rejection of claim 8, directed to a temperature in excess of 100°C, was reversed.). See also In re Peterson, 315 F.3d 1325, 1329-31, 65 USPQ2d 1379, 1382-85 (Fed. Cir. 2003) (data showing improved alloy strength with the addition of 2% rhenium did not evidence unexpected results for the entire claimed range of about 1-3% rhenium); In re Grasselli, 713 F.2d 731, 741, 218 USPQ 769, 777 (Fed. Cir. 1983) (Claims were directed to certain catalysts containing an alkali metal. Evidence presented to rebut an obviousness rejection compared catalysts containing sodium with the prior art. The court held this evidence insufficient to rebut the prima facie case because experiments limited to sodium were not commensurate in scope with the claims.).
Obviousness Type Double Patenting Rejections
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 51, 53-55, 57-60, and 62-63 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2, 8-10, 11 and 13 of U.S. Patent No. 9, 597,284 (‘284) in view of Ziegler (US20060084656, IDS reference) and Rollema et al. (Neurochemistry International 58 (2011) 78–84).
Instant claim 51 recites a method of activating a trigeminal nerve in a human in need thereof comprising administering a therapeutically effective amount of varenicline to the human, wherein said administration is local administration of a spray of a liquid pharmaceutical formulation comprising a solution of varenicline or a pharmaceutically acceptable varenicline salt and one or more pharmaceutically acceptable inactive ingredients, wherein the concentration of varenicline in the formulation is between about 0.1 mg/mL and about 10 mg/mL, into a nasal cavity of the human, wherein the therapeutically effective amount of varenicline administered into the nasal cavity is between 5 micrograms and 500 micrograms. Instant claim 52 recites the method of claim 51, wherein the varenicline administered selectively binds to peripheral nicotinic acetylcholine receptors. Instant claims 53-55, 57-60, and 62-63 recite amount or concentration of varenicline in microgram or mg/ml.
‘284 in claim 1 recites a method of treating dry eye, comprising the local administration of a therapeutically effective amount of a nicotinic acetylcholine receptor agonist into the nasal cavity of an individual in need thereof, wherein the agonist selectively binds to the peripheral nicotinic acetylcholine receptor, is administered in a non-systemically bioavailable dose between 5 micrograms and 50 micrograms per dose, and does not cross the blood-brain barrier in a pharmacologically relevant concentration; and wherein the nicotinic acetylcholine receptor agonist is varenicline. Claim 2 of ‘284 recites the method of claim 1, wherein the agonist selectively binds to at least one of the peripheral nicotinic acetylcholine receptor subtypes selected from alpha3beta4, alpha4beta2, and alpha7. Claims 8-10 of ‘284 recite frequency of administration. Claim 11 of ‘284 recites form of the composition which includes liquid and suspension. Claim 13 of ‘284 recites the method of claim 1, wherein the trigeminal nerve is activated.
The difference between instant claims 51, 53-55, 57-60, and 62-63 and claims 1, 2, 8-10, 11 and 13 of ‘284 is the instant application recites concentration of ‘284 is that instant claim 51 and dependent claims thereof recite the concentration of varenicline in mg/ml wherein the broadest being 0.1 mg/ml to 10 mg/ml. These deficiencies are cured by the teachings of Ziegler and Rollema et al.
Ziegler teaches varenicline binds to neuronal nicotinic acetylcholine specific receptor (nAChRs) sites and is useful in modulating cholinergic function. Accordingly, this compound is useful in the treatment of various conditions or diseases including, but not limited to, inflammatory bowel disease (including, but not limited to, ulcerative colitis, pyoderma gangrenosum and Crohn's disease), irritable bowel syndrome, spastic dystonia, chronic pain, acute pain, celiac sprue, pouchitis, vasoconstriction, anxiety, panic disorder, depression, bipolar disorder, autism, sleep disorders, jet lag, amyotrophic lateral sclerosis (ALS), cognitive dysfunction, hypertension, bulimia, anorexia, obesity, cardiac arrhythmias, gastric acid hypersecretion, ulcers, pheochromocytoma, progressive supranuclear palsy, chemical dependencies and addictions (e.g., dependencies on, or addictions to nicotine (and/or tobacco products), alcohol, benzodiazepines, barbiturates, opioids or cocaine), headache, migraine, stroke, traumatic brain injury (TBI), obsessive-compulsive disorder (OCD), psychosis, Huntington's chorea, tardive dyskinesia, hyperkinesia, dyslexia, schizophrenia, multi-infarct dementia, age-related cognitive decline, epilepsy, including petit mal absence epilepsy, senile dementia of the Alzheimer's type (AD), Parkinson's disease (PD), attention deficit hyperactivity disorder (ADHD) and Tourette's Syndrome (paragraph 0006). Ziegler teaches a composition for nasal administration comprising varenicline or its pharmaceutically acceptable salt and at least one excipient. The invention also provides a composition for buccal administration comprising varenicline or its pharmaceutically acceptable salt and at least one excipient to form a solid dosage form, wherein the solid dosage form disintegrates in an oral cavity at body temperature and may adhere to body tissue of the oral cavity; a composition for pulmonary administration comprising varenicline or its pharmaceutically acceptable salt and at least one excipient; and, a method for reducing nicotine addiction, aiding in the cessation of, or lessening of tobacco use in a subject (see abstract). The present invention has numerous embodiments. In any of the embodiments, pharmaceutical compositions of varenicline can be desirably administered in doses ranging from about 0.1 mgA up to about 6 mgA per day (where mgA refers to mg of active drug based on the free base form of the drug), more preferably from about 0.5 to 4 mgA/day, and most preferably from about 1 to 4 mgA per day in single or divided doses. Variations in such dosages, however, necessarily occur depending upon the weight and condition of the subject being treated. Depending on individual responses, dosage levels below the lower limit of the aforesaid range can be more than adequate, while in other cases still larger doses can be employed without causing any harmful side effects. The final pharmaceutical composition is processed into a unit dosage form and then packaged for distribution. The processing step varies depending upon the particular unit dosage form. For example, a tablet is generally compressed under pressure into a desired shape. Those of skill in the art are well aware of the procedures used for manufacturing the various unit dosage forms (paragraph 0030). A nasal spray solution is exemplified herein. Varenicline tartrate (1.5 g) is dissolved in 100 ml 0.05M Phosphate buffer (pH 4.4) and sufficient sodium chloride is added to the solution to make it isotonic. The solution is placed in a nasal administrator designed to deliver 100 μl of spray for each application. One spray in each nostril delivers a total of 3 mg of varenicline tartrate (approximately equivalent to 1.7 mg varenicline free base) (paragraph 0070, example 3). The total dosage amount is about 100 micrograms to about 6 mg, with a dose of 1.7 mg exemplified for intranasal administration (paragraphs 0030 and 0070). One can calculate an overall concentration of 1.7 mg varenicline free base per 100 μl of spray solution which is equivalent to 1.7 mg/0.1 ml which overlaps in scope with claimed concentrations. The intranasal administration is with one spray per nostril, i.e., delivered in alternating nostrils (paragraph 70). Thus, dose per spray (i.e., per nostril) would be about 50 micrograms to about 3 mg, with 865 micrograms exemplified. These ranges render obvious the claimed ranges. The intranasal compositions may also contain one or more preservatives selected from quaternary ammonium salts such as lauralkonium chloride, benzalkonium chloride etc. (paragraph 0045), the examiner notes that “may” entails the preservatives are optional with the broadest reasonable interpretation). Furthermore the examples such as example 3 do not contain a preservative in Ziegler et al.).
Rollema et al. teach that in view of the high comorbidity of nicotine dependence with mood disorders, this study investigated potential interactions of the smoking cessation agent varenicline with two antidepressant drugs, an SSRI (sertraline) and an MAOI (clorgyline), in a preclinical animal model (see conclusion). One of ordinary skill in the art would have been motivated to do so because Rollema et al. demonstrates the effective utilization of for instance 1 mg/ml concentration for varenicline. Rollema et al. teach that at least four pre-drug basal samples were collected before compounds were administered (varenicline, 1 mg/ml free-base in saline; clorgyline, 4 mg/ml free-base in saline; sertraline 17.8 mg/ml free-base in 20% solutol; all compounds and vehicles were administered s.c. in a volume of 1 ml/kg s.c.). Effects of each compound alone on monoamine dialysate levels were determined by administering varenicline, sertraline, clorgyline or corresponding vehicles and collecting 15-min samples for 4.5 h (see materials and methods section).
It would have been prima facie obvious before the effective filing date of the instant application to modify the teachings of “284 by utilizing varenicline in concentration of about 0.1 mg/ml and about 10 mg/ml and other concentrations because Ziegler et al. teach a nasal spray solution is exemplified herein. Varenicline tartrate (1.5 g) is dissolved in 100 ml 0.05M Phosphate buffer (pH 4.4) and sufficient sodium chloride is added to the solution to make it isotonic. The solution is placed in a nasal administrator designed to deliver 100 μl of spray for each application. One spray in each nostril delivers a total of 3 mg of varenicline tartrate (approximately equivalent to 1.7 mg varenicline free base) (paragraph 0070, example 3). The total dosage amount is about 100 micrograms to about 6 mg, with a dose of 1.7 mg exemplified for intranasal administration (paragraphs 0030 and 0070). One can calculate an overall concentration of 1.7 mg varenicline free base per 100 μl of spray solution which is equivalent to 1.7 mg/0.1 ml which overlaps in scope with claimed concentrations. The intranasal administration is with one spray per nostril, i.e., delivered in alternating nostrils (paragraph 70). Thus, dose per spray (i.e., per nostril) would be about 50 micrograms to about 3 mg, with 865 micrograms exemplified. These ranges render obvious the claimed ranges. The intranasal compositions may also contain one or more preservatives selected from quaternary ammonium salts such as lauralkonium chloride, benzalkonium chloride etc. (paragraph 0045). Furthermore, Rollema et al. teach that in view of the high comorbidity of nicotine dependence with mood disorders, this study investigated potential interactions of the smoking cessation agent varenicline with two antidepressant drugs, an SSRI (sertraline) and an MAOI (clorgyline), in a preclinical animal model (see conclusion). One of ordinary skill in the art would have been motivated to do so because Rollema et al. demonstrates the effective utilization of for instance 1 mg/ml concentration for varenicline. Rollema et al. teach that at least four pre-drug basal samples were collected before compounds were administered (varenicline, 1 mg/ml free-base in saline; clorgyline, 4 mg/ml free-base in saline; sertraline 17.8 mg/ml free-base in 20% solutol; all compounds and vehicles were administered s.c. in a volume of 1 ml/kg s.c.). Effects of each compound alone on monoamine dialysate levels were determined by administering varenicline, sertraline, clorgyline or corresponding vehicles and collecting 15-min samples for 4.5 h (see materials and methods section). The rationale to support a conclusion that the claim would have been obvious is that all the claimed elements were known in the prior art and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions, and the combination yielded nothing more than predictable results to one of ordinary skill in the art. KSR, 550 U.S. at 416, 82 USPQ2d at 1395; B/E Aerospace, Inc. v. C&D Zodiac, Inc., 962 F.3d 1373, 1379, 2020 USPQ2d 10706 (Fed. Cir. 2020); Sakraida v. AG Pro, Inc., 425 U.S. 273, 282, 189 USPQ 449, 453 (1976); Anderson’s-Black Rock, Inc. v. Pavement Salvage Co., 396 U.S. 57, 62-63, 163 USPQ 673, 675 (1969); Great Atl. & P. Tea Co. v. Supermarket Equip. Corp., 340 U.S. 147, 152, 87 USPQ 303, 306 (1950). Furthermore, in the case where the claimed ranges for the amounts and concentrations of active agent and other ingredients “overlap or lie inside ranges disclosed by the prior art” a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). Similarly, a prima facie case of obviousness exists where the claimed ranges and prior art ranges do not overlap but are close enough that one skilled in the art would have expected them to have the same properties. Titanium Metals Corp. of America v. Banner, 778 F.2d 775, 227 USPQ 773 (Fed. Cir. 1985). Furthermore, generally differences in concentration will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. “[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). It is within the purview of the skilled artisan to optimize the amounts of active agents and ingredients. The skilled artisan would have had a reasonable expectation of success in combining the teachings of ‘284, Ziegler, and Rollema et al. because all of the references teach varenicline containing compositions.
Claims 51, 53-55, 57-60, and 62-63 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 7-10, 12, 17-19, 22-24, 28-31, 33, 38-39, 41-44, 47-49, 52-53, 55-58, 61-62, 68-71, 74-75, 78-80, and 86-89 of U.S. Patent No. 10, 456,396 (‘396) in view of McCulloch et al. (Journal of Physiology, 516.2, pp. 471-484, 1999) and Akerman et al. (British Journal of Pharmacology, 2003, 140(4), 718-724).
Instant claim 51 recites a method of activating a trigeminal nerve in a human in need thereof comprising administering a therapeutically effective amount of varenicline to the human, wherein said administration is local administration of a spray of a liquid pharmaceutical formulation comprising a solution of varenicline or a pharmaceutically acceptable varenicline salt and one or more pharmaceutically acceptable inactive ingredients, wherein the concentration of varenicline in the formulation is between about 0.1 mg/mL and about 10 mg/mL, into a nasal cavity of the human, wherein the therapeutically effective amount of varenicline administered into the nasal cavity is between 5 micrograms and 500 micrograms. Instant claim 52 recites the method of claim 51, wherein the varenicline administered selectively binds to peripheral nicotinic acetylcholine receptors. Instant claims 53-55, 57-60, and 62-63 recite amount or concentration of varenicline in microgram or mg/ml.
‘396 in claims 1, 22, 38, 52, 61, and 79 recite a method of treating dry eye in an individual in need thereof, comprising administering different amounts of varenicline in micrograms in alternating nostrils of the individual. Claims 2, 23, 39, 53, 62, 80 recite further amounts in micrograms. Claims 3-4 and 24 recite varenicline selectively binding to a peripheral nicotinic acetylcholine receptor. Claims 7-9, 18, 28-30, 55-57, 68-70, and 86-88 of ‘396 recite frequencies of administration. Claims 17, 47 and 78 of ‘396 recite administering about 0.5 mg/mL of varenicline. Claims 12 and 33 of ‘396 recite the method of claim 1, wherein a trigeminal nerve is activated.
The difference between instant claims 51, 53-55, 57-60, and 62-63 and claims 1-3, 7-10, 12, 17-19, 22-24, 28-31, 33, 38-39, 41-44, 47-49, 52-53, 55-58, 61-62, 68-71, 74-75, 78-80, and 86-89 of ‘396 is ‘396 in independent claims 38, 52, 61, and 79 do not teach activating a trigeminal nerve in human by administering varenicline. This deficiency is cured by the teachings of McCulloch et al. and Akerman et al.
The teachings of McCulloch et al. and Akerman et al. are described above in detail and are incorporated herein by reference.
It would have been prima facie obvious before the effective filing date of the instant application to modify the teachings of ‘396 for a method of activating a trigeminal nerve in human by administering varenicline because McCulloch et al. teach chemical stimulation of the nasal mucosa in rats activates trigeminal nerve afferents, leading to physiological responses such as increased cerebral blood flow and systematic blood pressure via rostral ventolateral medulla (abstract and see page 471). This study use ammonia vapor as a chemical stimulant but demonstrates that trigeminal nerve ending in the nasal mucosa which express receptors including nAChRs are responsive to chemical agents (page 472). Similarly, Akerman et al. teach chemical stimulation of trigeminal sensory nerve fibers using capsaicin which induces physiological responses such as dural vasodilation via calcitonin gene related peptide release (abstract and page 718). While capsaicin targets TRPV1 receptors the study confirms that trigeminal nerve endings are amenable to chemical activation including in the nasal mucosa which is innervated by trigeminal branches (page 720). These teachings by Akerman also support the general principle of pharmacologically targeting trigeminal nerve receptors for therapeutic effects. One of ordinary skill in the art would have been motivated to do so because first ‘396 clearly teach that varenicline binds to neuronal nicotinic acetylcholine specific receptor (nAChRs) sites and is useful in modulating cholinergic function. McCulloch et al teach that nAChRs are expressed on trigeminal nerve endings, including the nasal mucosa (page 472). One of ordinary skill in the art would recognize that vareniclines action on nAChRs could extend to peripheral sites like the trigeminal nerve given its pharmacological profile. One of ordinary skill in the art, aware of varenicline’s nAChRs agonism based on ‘396 and the trigeminal nerve’s responsiveness to chemical stimulation via nasal administration as McCulloch et al. would have been motivated to administer varenicline to activate trigeminal nAChRs expecting physiological effects similar to those observed with other stimulants described by McCulloch et al. and Akerman et al. The nasal mucosa’s accessibility and trigerminal innervation provide a clear delivery route as validated by ‘396’s nasal spray. The combination of the references renders the instant invention obvious as it involves applying a known compound varenicline to a known target trigeminal nAChRs for a predictable outcome which is nerve activation. Furthermore, in the case where the claimed ranges for the amounts and concentrations of active agent and other ingredients “overlap or lie inside ranges disclosed by the prior art” a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). Similarly, a prima facie case of obviousness exists where the claimed ranges and prior art ranges do not overlap but are close enough that one skilled in the art would have expected them to have the same properties. Titanium Metals Corp. of America v. Banner, 778 F.2d 775, 227 USPQ 773 (Fed. Cir. 1985). Furthermore, generally differences in concentration will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. “[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). It is within the purview of the skilled artisan to optimize the amounts of active agents and ingredients. The skilled artisan would have had a reasonable expectation of success in combining the teachings of ‘396, McColloch, and Akerman because all of the references teach targeting nicotinic acetylcholine receptor (nAChRs).
Response to Arguments
Applicant argues Applicant intends to address the aforementioned rejections of claims over Patent ‘284 and over ‘396 by filing Terminal Disclaimers in due course.
The above assertions are not found persuasive because a request to hold a rejection in abeyance is not a proper response to a rejection. Rather, a request to hold a matter in abeyance may only be made in response to an OBJECTION or REQUIREMENTS AS TO FORM (see MPEP 37 CFR 1.111(b) and 714.02). Thus, the double patenting rejections of record have been maintained as no action regarding these rejections has been taken by applicants at this time.
Conclusion
No claim is allowed.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to TIGABU KASSA whose telephone number is (571)270-5867. The examiner can nor