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 .
Status of the Claims
Claims 1-9 are pending and examined.
Claim of Foreign Priority
Applicant’s claim of foreign priority is acknowledged. Certified copies of Applicant’s foreign priority documents were received in parent application serial no. 17/610,054.
The examiner notes that the claim set presented is identical to and/or substantially similar to the claim set of March 29, 2022, in now abandoned parent application serial no. 18/387,577. For consistency and propriety the rejection herein is based on the prior art cited in the non-final rejection of July 19, 2022, made in the ‘577 application.
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.
Claims 1-2 and 4-6 are rejected under 35 U.S.C. 103 as being unpatentable over Griñán-Ferré (Behavioral and Cognitive Improvement Induced by Novel Imidazoline I2 Receptor Ligands in Female SAMP8 Mice, Neurotherapeutics (2019) 16:416–431)(hereinafter Ferré), in view of Comi (Efficacy of CR4056, a first-in-class imidazoline-2 analgesic drug, in comparison with naproxen in two rat models of osteoarthritis, Journal of Pain Research 2017:10 1033–1043).
Griñán-Ferré teaches that as populations increase their life expectancy, age-related neurodegenerative disorders such as Alzheimer’s disease have become more common. I2-Imidazoline receptors (I2-IR) are widely distributed in the central nervous system, and dysregulation of I2-IR in patients with neurodegenerative diseases has been reported, suggesting their implication in cognitive impairment. This evidence indicates that high-affinity selective I2-IR ligands potentially contribute to the delay of neurodegeneration. See Abstract. In vivo studies in the female senescence accelerated mouse-prone 8 mice have shown that treatment with I2-IR ligands produce beneficial effects in behavior and cognition. Changes in molecular pathways implicated in oxidative stress, inflammation, synaptic plasticity, and apoptotic cell death were also studied. Furthermore, treatments with these I2-IR ligands diminished the amyloid precursor protein processing pathway and increased Aβ degrading enzymes in the hippocampus of SAMP8 mice. These results collectively demonstrate the neuroprotective role of these new I2-IR ligands in a mouse model of brain aging through specific pathways and suggest their potential as therapeutic agents in brain disorders and age-related neurodegenerative diseases. (abstract). Griñán-Ferré further teaches that I2-IR are involved in analgesia, glial tumors, inflammation and a plethora of brain disorders, such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and psychiatric disorders. A neuroprotective role for I2-IR was described through the pharmacological activities observed for their ligands. Idazoxan reduced neuron damage in the hippocampus after global ischemia in the rat brain and agmatine, identified as the endogenous I2-IR ligand [24], has demonstrated modulatory actions in several neurotransmitters that produce neuroprotection both in vitro and in rodent models. The efficacy of the analgesic CR4056 in osteoarthritis has advanced this compound in the first-in-class I2-IR ligand to achieve phase II clinical trials (page 417, left column, first paragraph). Griñán-Ferré discloses the use of two I2 imidazoline ligands (MCR9 and MCR5) in a model of Alzheimer’s disease.
Ferré does not teach 2-phenyl-6-(1H-imidazol-1-yl)quinazoline (CR4056) to treat Alzheimer’s disease.
Comi teaches that CR4056 is a newly described highly selective I2 receptor ligand. In a receptor characterization study including 35 common receptors, enzymes and ion channels, CR4056 shows high affinity at I2 receptors and MAO-A but negligible binding activity at all other sites, demonstrating its high receptor selectivity (page 1). CR4056 is a recently characterized imidazoline I2 receptor ligand that demonstrates high selectivity at I2 receptors over a panel of more than 35 other common receptors, enzymes and binding sites. CR4056 can readily cross the blood brain barrier and demonstrates strong antinociceptive activity in several rodent models of persistent inflammatory and neuropathic pain (page 4). CR4056 dose- and time-dependently produced discriminative stimulus effects, with the highest dose slightly but significantly reducing the rate of responding (Fig. 1). When tested with different doses, CR4056 increased responding on the CR4056-associated lever in a dose-dependent manner, ranging from 1% after vehicle injection to a maximum of 98% after injecting with the training dose of 10 mg/kg CR4056 [ED50 (95% CLs) 5 5.0 (4.0, 5.9) mg/kg] (upper left panel, open circles), with the dose of 10 mg/kg slightly but significantly reducing response rate (lower left panel, open circles). Oral administration of CR4056 only slightly reduced its potency for producing CR4056-appropriate lever responding [ED50 (95% CLs) 5 9.2 (4.7, 12.5) mg/kg] (upper left panel, open squares) and CR4056 significantly decreased rate of responding at the highest oral dose tested (17.8 mg/kg) (lower left panel, open squares). In tests to examine the duration of action of the training dose of CR4056 (i.e., 10 mg/kg, i.p.), drug was administered with varying pretreatment times. It was found that the discriminative stimulus effects of CR4056 were apparent after 5 min pretreatment, reached the maximal effect after 30 min pretreatment and decreased to 12% 5 hours later (top rightpanel), with response rate slightly but significantly decreased at 20 and 30 min time points.
It would have been obvious to one of ordinary skill in the art prior to the filing of the instant application to arrive at the claimed methods in view of the cited prior art. One would have been motivated to substitute CR4056 as the specific I2-Imidazoline inhibitor because it is known in the art that CR4056 is a newly described highly selective I2 receptor ligand as disclosed by Giordani. Additionally, it is known that I2-Imidazoline receptors (I2-IR) are widely distributed in the central nervous system, and dysregulation of I2-IR in patients with neurodegenerative diseases has been reported, suggesting their implication in cognitive impairment. This evidence indicates that high-affinity selective I2-IR ligands potentially contribute to the delay of neurodegeneration as taught by Ferré with a reasonable expectation of success. If would be further obvious to optimize the dosing of CR4056 since it is known in the art to administer CR4056 in increased responding on the CR4056-associated lever in a dose-dependent manner, ranging from 1% after vehicle injection to a maximum of 98% after injecting with the training dose of 10 mg/kg CR4056 [ED50 (95% CLs) 5 5.0 (4.0, 5.9) mg/kg] (upper left panel, open circles), with the dose of 10 mg/kg slightly but significantly reducing response rate (lower left panel, open circles). In the case where the claimed ranges "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) (The prior art taught carbon monoxide concentrations of "about 1-5%" while the claim was limited to "more than 5%." The court held that "about 1-5%" allowed for concentrations slightly above 5% thus the ranges overlapped.); In re Geisler, 116 F.3d 1465, 1469-71, 43 USPQ2d 1362, 1365-66 (Fed. Cir. 1997) (Claim reciting thickness of a protective layer as falling within a range of "50 to 100 Angstroms" considered prima facie obvious in view of prior art reference teaching that "for suitable protection, the thickness of the protective layer should be not less than about 10 nm [i.e., 100 Angstroms]." The court stated that "by stating that ‘suitable protection’ is provided if the protective layer is ‘about’ 100 Angstroms thick, [the prior art reference] directly teaches the use of a thickness within [applicant’s] claimed range."). 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) (Court held as proper a rejection of a claim directed to an alloy of "having 0.8% nickel, 0.3% molybdenum, up to 0.1% iron, balance titanium" as obvious over a reference disclosing alloys of 0.75% nickel, 0.25% molybdenum, balance titanium and 0.94% nickel, 0.31% molybdenum, balance titanium.). "[A] prior art reference that discloses a range encompassing a somewhat narrower claimed range is sufficient to establish a prima facie case of obviousness." In re Peterson, 315 F.3d 1325, 1330, 65 USPQ2d 1379, 1382-83 (Fed. Cir. 2003). See also In re Harris, 409 F.3d 1339, 74 USPQ2d 1951 (Fed. Cir. 2005)(claimed alloy held obvious over prior art alloy that taught ranges of weight percentages overlapping, and in most instances completely encompassing, claimed ranges; furthermore, narrower ranges taught by reference overlapped all but one range in claimed invention). However, if the reference’s disclosed range is so broad as to encompass a very large number of possible distinct compositions, this might present a situation analogous to the obviousness of a species when the prior art broadly discloses a genus. Id. See also In re Baird, 16 F.3d 380, 29 USPQ2d 1550 (Fed. Cir. 1994); In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992); MPEP § 2144.08.
Claim 3 is rejected under 35 U.S.C. 103 as being unpatentable over Griñán-Ferré (Behavioral and Cognitive Improvement Induced by Novel Imidazoline I2 Receptor Ligands in Female SAMP8 Mice, Neurotherapeutics (2019) 16:416–431)(hereinafter Ferré) of record in view of Comi (Efficacy of CR4056, a first-in-class imidazoline-2 analgesic drug, in comparison with naproxen in two rat models of osteoarthritis, Journal of Pain Research 2017:10 1033–1043) as applied to claims 1-2, 4-6 above, and further in view of Giordani (U.S. Patent 7,994,181).
Griñán-Ferré and Comi as cited above.
Neither Griñán-Ferré nor Comi disclose CR4056 in a salt form.
Giordani teaches that inflammation causes the induction of COX-2, leading to the release of prostanoids, which sensitize peripheral nociceptor terminals and produce localized pain hypersensitivity, however peripheral inflammation also generates central sensitization by direct widespread induction of COX-2 expression in spinal cord and CNS neurons. Giordani teaches that CR4056 (example 1 and 2) may be in a pharmaceutically acceptable salt selected from the group consisting of hydrochloride, hydrobromide, hydrogensulphate and sulphate, maleate, fumarate, oxalate, methanesulfonate, succinate, ascorbate, tartrate (claim 6). Giordani teaches that example 1 (CR4056) is administered in dosages of 3, 10 and 30 mg/kg (Table 5 and Table 6).
It would have been obvious to one of ordinary skill in the art prior to the filing of the instant application to use CR4056 in a claimed pharmaceutically acceptable salt form. One would have been motivated to have CR4056 in pharmaceutical salt form because it is known that CR4056 in salt forms (hydrochloride, hydrobromide, hydrogensulphate and sulphate, maleate, fumarate, oxalate, methanesulfonate, succinate, ascorbate, tartrate) is effective in treatment.
Claims 7-9 are rejected under 35 U.S.C. 103 as being unpatentable over Griñán-Ferré (Behavioral and Cognitive Improvement Induced by Novel Imidazoline I2 Receptor Ligands in Female SAMP8 Mice, Neurotherapeutics (2019) 16:416–431)(hereinafter Ferré) of record in view of Comi (Efficacy of CR4056, a first-in-class imidazoline-2 analgesic drug, in comparison with naproxen in two rat models of osteoarthritis, Journal of Pain Research 2017:10 1033–1043) as applied to claims 1-2, 4-6 above, and further in view of Knowles (Donepezil in Alzheimer’s disease: an evidence-based review of its impact on clinical and economic outcomes, 2006, Clinical impact review).
Griñán-Ferré and Comi as cited above.
Neither Griñán-Ferré nor Comi disclose at least one further drug.
Knowles teaches that Donepezil is indicated for the symptomatic treatment of mild to moderate Alzheimer’s disease. It is a specific and reversible inhibitor of acetylcholinesterase (AChE); by increasing levels of available acetylcholine, donepezil may compensate for the loss of functioning cholinergic brain cells (abstract).
It would have been obvious to one of ordinary skills in the art prior to the filing of the instant application to combine CR4056 and donepezil together to treat Alzheimer’s disease. As stated in In re Kerkhoven, 626 F.2d 846, 205 USPQ 1069, at page 1072 (CCPA 1980):
It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition which is to be used for the very same purpose. In re Susi, 58 CCPA 1074, 1079-80, 440 F.2d 442, 445, 169 USPQ 423, 426 (1971); In re Crockett, 47 CCPA 1018, 1020-21, 279 F.2d 274, 276-77, 126 USPQ 186, 188 (CCPA 1960). As this court explained in Crockett, the idea of combining them flows logically from their having been individually taught in the prior art. Therefore, it would have been prima facie obvious to combine CR4056 and donepezil composition cojointly in a formulation to treat Alzheimer’s disease.
Regarding the limitation of simultaneously, sequentially or separately administering a combined pharmaceutical preparation comprising 2-phenyl-6-(1H-imidazol-1-yl)quinazoline (CR4056) or a pharmaceutically acceptable salt thereof and at least one of NMDA (N-methyl-D-aspartic acid) receptor antagonists and/or acetylcholinesterase inhibitors. The instant situation is amenable to the type of analysis set forth in Ex parte Rubin , 128 USPQ 440 (Bd. App. 1959) and also In re Burhans, 154 F.2d 690, 69 USPQ 330 (CCPA 1946), where the court found that the selection of any order of performing process steps is prima facia obvious in the absence of new or unexpected results. As such, applying the same logic to the instant process claims, one of ordinary skill in the art would have a reasonable expectation that by administering a formulation comprising CR4056 and donepezil simultaneously, sequentially or separately, one would achieve a method of treating neurodegenerative disease (e.g. Alzheimer’s disease) with a reasonable expectation of success.
For these reasons, the claimed subject matter is deemed to fail to be patentably distinguishable over the state of the art as represented by the cited reference. The claims are therefore, properly rejected under 35 U.S.C. 103.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(a).
From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JARED D BARSKY whose telephone number is (571)272-2795. The examiner can normally be reached on 9-5 M-F.
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/JARED BARSKY/Primary Examiner, Art Unit 1628