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
The status of the claims are as follows:
Claims 19-35 are pending.
Claims 19-35 are rejected.
Priority
Acknowledgement is made that Instant Application 18/863,395, filed on 11/06/2024, is a National Stage Entry of PCT/SE2023/050447, filed on 05/08/2023, which claims priority from Provisional Application 63/340,567, filed on 05/11/2022.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 11/06/2024 and 04/22/2026 is/are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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 text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
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.
Claim(s) 19-22 and 26-28 is/are rejected under 35 U.S.C. 103 as being unpatentable over Olive (US 2015/0141462 A1. Published 05/21/2015).
Claim 19 is directed to a combination comprising an effective amount of varenicline, or a salt thereof, and an effective amount of a glycine transport (GlyT) inhibitor.
Olive teaches pharmaceutical compositions and methods for treating drug addiction and preventing a drug relapse comprising administering a pharmaceutical composition comprising (a) a mGluR5 positive allosteric modulator derivative, prodrug or a pharmaceutically acceptable salt thereof; (b) a pharmaceutically effective amount of an agent selected from an NMDA partial agonist or a GlyT1 inhibitor, derivative, prodrug or a pharmaceutically acceptable salt thereof; and (c) a pharmaceutically acceptable carrier (title, abstract). Olive further teaches in some embodiments, the pharmaceutically acceptable composition further comprises an additional agent useful in treating drug addiction or preventing drug relapse in the patient, which can be selected as varenicline for nicotine addiction (page 6, paragraph 0061).
While Olive does not explicitly teach the Instantly-recited combination, one of ordinary skill in the art could have applied the prong (A) rationale of In re KSR Int’l Co., 550 U.S. 398 (2007) to arrive at a pharmaceutical composition comprising a mGluR5 positive allosteric modulator, a GlyT1 inhibitor, and varenicline to use as a treatment option for nicotine addiction. Therefore, a combination comprising varenicline and a GlyT inhibitor is rendered prima facie obvious.
Claim 20-22 are directed to the combination of claim 19, wherein the combination is formulated for sequential, simultaneous, and separate administration, respectively.
Olive teaches the mGluR5 positive allosteric modulators and GlyT1 inhibitors or the present invention may also be co-administered with additional therapeutic agents, which may be administered sequentially (e.g., separately) or concurrently to the patient (page 6, paragraph 0066).
Claim 26 is directed to the combination of claim 19, wherein the GlyT inhibitor is a GlyT1 inhibitor.
The pharmaceutical compositions of Olive comprise a GlyT1 inhibitor (abstract).
Claims 27-28 are directed to the combination of claim 26, wherein the GlyT1 inhibitor is selected as a compound from the provided group, wherein the compound is selected as N-methyl-N-[(3R)-3-phenyl-3-[4-(trifluoromethyl)phenoxy]propyl]-glycine.
Olive teaches the GlyT1 inhibitor is selected from the group comprising N-methyl-N-[(3R)-3-phenyl-3-[4-(trifluoromethyl)phenoxy]propyl]-glycine (Org 24598) (page 2, paragraph 0013).
While Olive does not teach an explicit embodiment wherein the GlyT1 inhibitor is Org 24598, one of ordinary skill in the art could have applied the prong (B) rationale of In re KSR Int’l Co., 550 U.S. 398 (2007) to substitute the GlyT1 inhibitor with Org 24598. Therefore, a combination comprising Org 24598 and varenicline is rendered prima facie obvious.
Claim(s) 23 and 25 is/are rejected under 35 U.S.C. 103 as being unpatentable over Olive in view of FDA (Chantix® package insert. Retrieved through WayBackMachine, 02/16/2017. https://web.archive.org/web/20170216190324/http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/021928s028lbl.pdf).
Claim 23 is directed to the combination according to claim 19, wherein the effective amount of varenicline is between 0.5 mg/day to 5 mg/day.
The teaching of Olive is discussed above and incorporated herein by reference.
The difference between the teaching of Olive and the Instant Application is that Olive fails to teach the dosage of the additional agent (e.g., varenicline).
However, FDA teaches the recommended dose of Chantix® (varenicline) as an aid to smoking cessation is 0.5 mg once daily in the evening (days 1-3), 0.5 mg twice daily (days 4-7), and 1 mg twice daily (days 8-end of treatment) (page 2, left column, “dosage and administration”).
One of ordinary skill in the art would have been motivated to combine the above teachings because they are both in the same field of endeavor. Olive teaches pharmaceutical compositions for treating drug addiction (e.g., nicotine addiction) that may comprise varenicline, while FDA teaches the recommended dose of varenicline to aid in smoking cessation. Therefore, one of ordinary skill in the art would have used the recommended dosage of FDA in the method taught by Olive to formulate a pharmaceutical composition to treat nicotine addiction.
Claim 25 is directed to the combination of claim 19 wherein the salt of varenicline is varenicline tartrate.
The teaching of Olive is discussed above and incorporated herein by reference.
The difference between the teaching of Olive and the Instant Application is that Olive fails to teach the use of varenicline tartrate.
However, FDA teaches Chantix® tablets contain varenicline as the tartrate salt (page 5, right column, “Description”).
One of ordinary skill in the art would have been motivated to combine the above teachings because they are both in the same field of endeavor. Olive teaches pharmaceutical compositions comprising varenicline and their use in treating nicotine addiction, while FDA teaches the varenicline tartrate salt is an approved pharmaceutical salt in treating the same. Therefore, said skilled artisan would have found it prima facie obvious to employ varenicline tartrate in the pharmaceutical composition taught by Olive to treat nicotine addiction.
Claim(s) 24 is/are rejected under 35 U.S.C. 103 as being unpatentable over Olive as evidenced by Fryar (Mean Body Weight, Weight, Waist Circumference, and Body Mass Index Among Adults: United States, 1999-2000 through 2015-2016. National Health Statistics Reports, 2018).
Claim 24 is directed to the combination of claim 19, wherein the effective amount of the GlyT inhibitors is selected within a range of 5 mg/day up to 150 mg/day.
While Olive does not specifically state the effective amount of the GlyT inhibitor, it is taught that the dosage levels of the active ingredient compounds are most preferably present in the composition between about 1 and 50 mg/kg body weight per day. In 2015-2016, the average adult male weighed about 90 kg and the average adult female weight about 77 kg (see Fryar, page 2, right column, paragraph 4). Therefore, the amount of GlyT present in the composition of Olive encompasses the instantly claimed range.
Claims 29-31 is/are rejected under 35 U.S.C. 103 as being unpatentable over AlSharai (The Antinociceptive Effects of Nicotinic Partial Agonists Varenicline and Sazetidine-A in Murine Acute and Tonic Pain Models. J. Pharmacol. Exp. Ther. 2012, 342, 742-749. Doi: 10.1124/jpet.112.194506) in view of Mingorance-Le (Reversible Inhibition of the Glycine Transporter GlyT2 Circumvents Acute Toxicity While Preserving Efficacy in the Treatment of Pain. Br. J. Pharmacol., 2013, 170, 1053-1063. Doi doi.org/10.1111/bph.12343).
Claims 29-31 are directed to the combination according to claim 19, wherein the GlyT inhibitor is a GlyT2 inhibitor, wherein the GlyT2 inhibitor is selected from a compound from the provided list, wherein the compound is selected as N-[[1- (dimethylamino)cyclopentyl]methyl]-3,5-dimethoxy-4-(phenylmethoxy)benzamide hydrochloride (Org 25543).
AlSharai teaches the antinociceptive effects of two nicotinic partial agonists, including varenicline, as compared to nicotine in acute and tonic mouse pain models (page 747, left column, paragraph 1). Varenicline did not show significant antinociceptive effects in the acute thermal models (tail-flick and hot-plate tests) (page 744, Fig 1A–Fig 1C), but it was effective in the formalin test: a persistent and tonic pain model (page 747, left column, paragraph 1 and page 746, Fig2A). The antinociceptive effects were reversed when mice were pretreated with intrathecal α-conotoxin AuIB, a selective α3β4 nAChR antagonist (page 748, left column, paragraph 2. Fig 3B). However, it is noted that its effectiveness is limited by unacceptable side effects at high doses including body temperature, locomotion, and responding for food (page 748, right column, paragraph 1).
The difference between AlSharai and the instant claims is that AlSharai fails to teach the use of a GlyT2 inhibitor, wherein the GlyT2 inhibitor Is Org 25543.
However, Mingorance-Le teaches the use of neuronal GlyT2 inhibitors, specifically Org 25543, as a treatment for chronic pain (page 1053, “background and purpose” and “experimental approach”). Org 25543 was administered to mice 5 min prior to formalin injection, resulting in decreased paw licking time during the late phase in a dose-dependent manner (page 1056, left column, paragraph 2 and Fig 2). Efficacy of a test compound during the late phase in the formalin model is regarded as predictive of efficacy in neuropathic pain (page 1056, left column, paragraph 2). However, it is noted that doses of 20 mg/kg was highly toxic, leading to convulsions and lethality (page 1056, left column, paragraph 2).
One of ordinary skill in the art would have been motivated to combine the teachings above because they are both in the same field of endeavor of treating neuropathic pain, as evidenced by showing efficacy in ameliorating pain in the mouse formalin test. Moreover, both drugs act on different receptors (i.e., varenicline is an α3β4 nAChR agonist and Org 25543 is a GltT2 inhibitor) and caused unwanted adverse events at high concentrations. Therefore, said artisan would have had a reasonable expectation of success to avoid the adverse events of either drug through at least an additive effect of their combination to treat the same indication.
Claim(s) 32-35 is/are rejected under 35 U.S.C. 103 as being unpatentable over Olive in view of Hong (Effects of Moderate-Dose Treatment with Varenicline on Neurobiological and Cognitive Biomarkers in Smokers and Nonsmokers with Schizophrenia or Schizoaffective Disorder. Arch Gen Psychiatry. 2011, 68(12), 1195-1206. Doi: 10.1001/archgenpsychiatry.2011.83) in view of Chue (Glycine Reuptake Inhibition as a New Therapeutic Approach in Schizophrenia: Focus on the Glycine Transporter 1 (GlyT1). Current Pharmaceutical Design, 2013, 19(7), 1311-1320. Doi: 10.2174/138161213804805766).
Claim 32 is directed to a method for treatment of schizophrenia comprising administering a combination according to claim 19 to a subject suffering from schizophrenia.
As discussed above, by applying prong (A) of the KSR rationale, Olive renders obvious a pharmaceutical composition comprised of three active ingredients: 1) a mGluR5 positive allosteric modulator; 2) a GlyT1 inhibitor; and 3) varenicline.
Olive further teaches positive allosteric modulation of mGluR5 receptors have been the focus for the treatment of CNS disorders, including schizophrenia (page 2, paragraph 0007).
The difference between the teaching of Olive and the Instant Application is that Olive fails to teach whereby the composition comprising a GlyT1 inhibitor and varenicline can be used as a method of treating schizophrenia.
However, Chue teaches glycine reuptake inhibition as a therapeutic approach for schizophrenia (title). Of the glycine transporters, GlyT1 is one of the more promising therapeutic targets in schizophrenia and there is evidence to support the premise that glycine inhibitor-mediated enhancement of NMDAR function is associated with an antipsychotic-like profile (page 1313, right column, paragraph 1). Specifically, Org 25935 is noted as a GlyT1 inhibitor with preclinical data (page 1315, Table 1).
One of ordinary skill in the art would have been motivated to combine the above teachings because they teach different uses for the same compound. The GlyT1 inhibitor of the pharmaceutical composition of Olive may be selected as Org 25935 (page 2, paragraph 0013), which is taught by Chue to be pharmaceutically relevant in treating schizophrenia. Furthermore, the primary active agent in the pharmaceutical composition of Olive (a positive allosteric modulator of mGluR5 receptor) is also known to be effective in treating schizophrenia. Therefore, one of ordinary skill in the art would have been drawn to the teaching of Chue to use the same composition in treating other CNS disorders.
The difference between the teaching of Olive in view of Chue and the Instant Application is that the combined teaching fails to teach whereby the composition comprising varenicline can be used as a method of treating schizophrenia.
However, Hong teaches the effect of varenicline on key biomarkers that are associated with schizophrenia (page 1, “objective”). In a double-blind, parallel, randomized, placebo controlled trial, the effects of varenicline on said biomarkers were examined on smoking and nonsmoking patients at 2 weeks and 8 weeks using a slow titration and moderate dosing strategy (page 1, “design”). It was found that moderate dose varenicline for 8-weeks provided a long-term neurobiological improvement on sensory gating and antisaccade functions, and a nonsignificant reduction in psychotic symptoms (page 1204, paragraph 2).
One of ordinary skill in the art would have been motivated to combine the above teachings because they teach different uses for the same compound. The pharmaceutical composition of Olive is comprised of varenicline, which is taught by Hong to have long-term improvement on some key biomarkers associated with schizophrenia. Furthermore, the two primary active agents in the pharmaceutical composition of Olive are known in the art to treat schizophrenia. Therefore, one of ordinary skill in the art would have been drawn to the teaching of Hong to apply the same composition in the treatment of other CNS disorders.
Accordingly, the three active agents in the pharmaceutical composition rendered obvious by Olive are all known in the art to treat schizophrenia. Therefore, one of ordinary skill in the art would have found it obvious to try a composition comprised of 1) a mGluR5 positive allosteric modulator; 2) a GlyT1 inhibitor (Org 25935); and 3) varenicline as a method of treating schizophrenia.
Regarding claims 33-35, it is noted that, as discussed above, the claimed product/method has been rendered obvious by Olive in view of Chue and in view of Hong, and thus the properties (such as alleviation of schizophrenia symptoms) are considered characteristic features of the claimed product.
It is further noted that MPEP 2112 discusses the support of rejections wherein the prior art discloses subject matter which there is reason to believe inherently includes functions that are newly cited or is identical to a product instantly claimed. In such a situation the burden is shifted to the applicants to "prove that subject matter shown to be in the prior art does not possess characteristic relied on" (205 USPQ 594, second column, first full paragraph). In the present case the burden is shifted to Applicant to prove that a composition comprising a mGluR5 positive allosteric modulator, the GlyT1 inhibitor Org 24598, and varenicline, does not inherently possess the same properties as the instantly claimed product.
Applicant is reminded that “Products of identical chemical composition cannot have mutual exclusive properties.” Any properties exhibited by or benefits from are not given any patentable weight over the prior art provided the composition is inherent. A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the disclosed properties are necessarily present. In re Spada, 911 F.2d 705, 709, 15 USPQ 1655, 1658 (Fed. Cir. 1990). See MPEP 2112.01. The burden is shifted to the applicant to show that the prior art product does not inherently possess the same properties as the instantly claimed product.
Conclusion
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/P.A./Examiner, Art Unit 1621
/CLINTON A BROOKS/Supervisory Patent Examiner, Art Unit 1621
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