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 Claims
Claims 1-2, 4, 8, 10, 15-16, 18, 22, 24, 29 and 46-54 are pending in the instant application.
Information Disclosure Statement (IDS)
The Information Disclosure Statement (IDS) filed 09/12/2025 was considered by the Examiner.
Continued Examination Under 37 CFR 1.114
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 September 12th, 2025 has been entered.
Restriction/Election
Search and examination has been limited as previously discussed in the Office action dated August 27th, 2024. Examination is limited to the extent that claims 1-4, 8, 10, 15-16, 18, 22, 24, 29 and 46-54 are readable on elected group I, a method of treating a disorder associated with a sleep spindle deficit with the elected disease of schizophrenia and the elected group II metabotropic glutamate receptor modulator, LY379268. Since the elected species is not allowable, subject matter not embraced by the elected embodiment is therefore withdrawn from further consideration.
Response to Remarks
Applicant’s amendments and arguments have overcome the rejections presented in the previous Office action.
Claim Objections
Claim 1 is objected to because of the following informalities:
It is recommended that Applicant amend the claim to recite “administering the subject…” in line 5 of the claim.
Claim 15 is objected to because of the following informalities:
It is recommended that Applicant amend the claim to recite “and determining that the subject has a mutation…” in line 5 of the claim.
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 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) 1, 2, 4, 8, 10, 47, 49, 51 and 53 is/are rejected under 35 U.S.C. 103 as being unpatentable over Johnson et al (WO 03/084610) in view of Lustenberger et al (Front. Neurol., 12 May 2012, 3).
Determining the scope and contents of the prior art. (See MPEP § 2141.01)
Johnson teaches a method for treating a patient suffering from a psychiatric disorder, comprising administering to said patient olanzapine in combination with (1R, 4R, 5S, 6R)-4-amino-(2-oxabicyclo [3.1.0]hexane)-4,6-dicarboxylic acid (claim 14). Johnson further teaches that the psychiatric disorder is schizophrenia (page 16, paragraph 3). (1R, 4R, 5S, 6R)-4-amino-(2-oxabicyclo [3.1.0]hexane)-4,6-dicarboxylic acid is LY 379268, as defined in Table 1 of the instant specification.
Ascertainment of the differences between the prior art and the claims. (See MPEP § 2141.02)
The prior art does not teach that method of treating schizophrenia includes determining that the subject has, is suspected of having or is at risk of developing a disorder associated with a sleep spindle deficit by detecting one or more characteristics of sleep spindles.
Finding of prima facie obviousness --- rationale and motivation (See MPEP § 2142-2143)
However, Johnson teaches that “a first step in treating humans is generally determining that a particular patient exhibits the symptoms of psychotic behavior such as schizophrenia” (page 22, Example 22). Further, Johnson teaches that “this determination is made by a person skilled in the art using a number of readily available diagnostic procedures (page 22, Example 2).
Further, Lustenberger teaches that topographical differences in sleep spindle activity of schizophrenic subjects. Lustenberger teaches that the reduced sleep spindle activity over centroparietal areas reflect dysfunction of thalamic reticular and thalamocortical mechanisms and represents a biological marker of illness (page 5, left column, paragraph 2). Lustenberger teaches this as an example showing the fruitfulness of applying hdEEG sleep recordings in clinical populations, when specifically concerned with subjects with schizophrenia (page 5, left column, paragraph 2).
Regarding claim 1, as Johnson teaches a method of treating schizophrenia comprising administering olanzapine and LY 379268 and determining that the patient exhibits symptoms of schizophrenia one of ordinary skill in the art would have been motivated to detect a characteristic of sleep spindles as Lustenberger teaches that analysis of sleep spindle activity, with an EEG, is a maker of schizophrenia.
Regarding claims 2 and 4, as seen above, Johnson teaches the administration of LY 379268.
Regarding claim 8, the claim recites “wherein the mGlu3 PAM is selected from…”, however, the method of treating schizophrenia taught by Johnson uses LY379268, which is an mGlu2/3 agonist, not a mGlu3 PAM. The claim from which claim 8 depends on, claim 1, recites that the group II metabotropic glutamate receptor can be a mGlu2/3 agonist or an mGlu3 specific PAM. As the limitations of claim 8 are to the mGlu3 PAM, the method of treating schizophrenia with LY379268 reads on the claim.
Regarding claim 10, as seen above, Johnson teaches that the subject has schizophrenia.
Regarding claim 47, as seen above, Lustenberger teaches that sleep spindle activity is a biomarker for schizophrenia.
Regarding claim 49, as seen above, Lustenberger teaches that subjects with schizophrenia display reduced sleep spindle activity.
Regarding claims 51 and 53, as seen above, Lustenberger teaches that the sleep spindle activity is measured with an EEG.
Claim(s) 15-16, 22, 24, 29, 46, 48, 50, 52 and 54 is/are rejected under 35 U.S.C. 103 as being unpatentable over Downing et al (WO 2010/111080 A2) in view of and Keshavan (Prog Neurobiol. 2017 May ; 152: 3–20), Andrade et al. (Sci Rep 6, 34233 (2016)) and Manoach et al (Biol Psychiatry. 2016 October 15; 80(8): 599–608).
Determining the scope and contents of the prior art. (See MPEP § 2141.01)
Downing teaches an optimized treatment of schizophrenia with group II metabotropic glutamate (mGlu) receptor agonists wherein genetic variants are used to predict the clinical outcome (page 1, paragraph 1). Downing teaches a method of treating schizophrenia that comprises obtaining a DNA sample from the patient, determining whether one or more single nucleotide polymorphisms is present in the patient and then administering an effective amount of a group II metabotropic glutamate (mGlu) receptor agonist to the patient, wherein the agonist is LY2140023 (claim 31).
Downing also teaches that a medical need exists to identify patients that will best respond to treatment regimens for schizophrenia by using genetic variants to predict the clinical outcome of therapy (page 2, paragraph 2). Downing further teaches that there exists a need to have methods for predetermining or quickly determining if a patient will likely respond to treatment for schizophrenia with a Group II mGlu receptor agonist compound (page2, paragraph 2).
Ascertainment of the differences between the prior art and the claims. (See MPEP § 2141.02)
The prior art does not explicitly teach a single embodiment wherein the mutation is in the gene encoding the CACNA1I protein at the amino reside corresponding to the amino acid residue 1346 in the CACNA1I protein. The prior art also does not teach that the method of treating schizophrenia includes determining that the subject has, is suspected of having or is at risk of developing a disorder associated with a sleep spindle deficit by detecting one or more characteristics of sleep spindles.
Finding of prima facie obviousness --- rationale and motivation (See MPEP § 2142-2143)
However, Keshavan teaches that there are genes implicated in schizophrenia that are considered to be “druggable” genes. The genes include DRD2 and CACNA1I (page 20, paragraph 1).Also, Andrade teaches that the CACNA1I gene features a missense variation of R1346H in patients with schizophrenia (page 1, paragraph 3).
Further, Manoach teaches that reduced spindle activity in schizophrenia is an endophenotype that impairs sleep dependent memory consolidation, contributes to symptoms and is a novel treatment biomarker (abstract). Manoach further teaches that this analyzing this link, one can advance the diagnosis, mechanistic understanding, treatment and prevention of schizophrenia (abstract). Also Manoach teaches that the sleep spindle activity is usually conducted with the sleep electroencephalogram (EEG) (page 3, paragraph 4).
Thus, regarding claim 15, one of ordinary skill in the art would have been motivated by the general teachings of Downing to include the gene mutation to be found in Downing to be a substitution of R134H of the CACNA1I protein as Kreshvan teaches that the CACNA1I is a druggable gene in schizophrenia and Andrade teaches that the CACNA1I gene features a missense variation of R1346H in patients with schizophrenia and also determine that the subject has schizophrenia by looking at sleep spindle characteristics as Manoach teaches that to advance the treatment and understanding of schizophrenia it is important to understand sleep spindle activity to improve the diagnosis and treatment of schizophrenia.
Regarding claim 16, as seen above, Downing teaches that the modulator is LY2140023.
Regarding claim 22, the claim recites “wherein the mGlu3 PAM is selected from…”, however, the method of treating schizophrenia taught by Downing uses LY2140023, which is an mGlu2/3 agonist, not a mGlu3 PAM. The claim from which claim 22 depends on, claim 16, recites that the group II metabotropic glutamate receptor can be a mGlu2/3 agonist or an mGlu3 specific PAM. As the limitations of claim 22 are to the mGlu3 PAM, the method of treating schizophrenia with LY2140023 reads on the claim.
Regarding claim 24, Downing teaches that the patient is preferably a human (page 12).
Regarding claim 29, as seen above, the disorder is schizophrenia.
Regarding claim 46, as seen above, the mutation in the gene encoding the CACNA1I protein substitution of R1346H is found in patients with schizophrenia. Thus, it would have been obvious to one of ordinary skill in the art to look for this substitution in Downing’s optimized treatment of schizophrenia.
Regarding claim 48, Manoach teaches that sleep spindle activity is detected.
Regarding claim 50, Manoach teaches that reduced sleep spindle activity is found in patients with schizophrenia (page 2, paragraph 4).
Regarding claims 52 and 54, Manoach teaches that an EEG is used to detect sleep spindle activity.
Claim(s) 18 is/are rejected under 35 U.S.C. 103 as being unpatentable over Downing et al (WO 2010/111080 A2) in view of and Keshavan (Prog Neurobiol. 2017 May ; 152: 3–20), Andrade et al. (Sci Rep 6, 34233 (2016)) and Manoach et al (Biol Psychiatry. 2016 October 15; 80(8): 599–608)and in further view of Imre et al (Pharmacology, Biochemistry and Behavior 84 (2006) 392–399).
The 103 rejection of claims 15-16, 22, 24, 29, 46, 48, 50, 52 and 54 over Downing, Keshavan and Manoach is incorporated herein by reference.
Determining the scope and contents of the prior art. (See MPEP § 2141.01)
Downing does not explicitly teach that the compound used in the method of treating schizophrenia is LY379268. However, Downing teaches that the mGlu receptor agonist contains a bicyclohexane or heterobicyclohexane ring system (page 6, paragraph 2).
Ascertainment of the differences between the prior art and the claims. (See MPEP § 2141.02)
The prior art does not explicitly teach a single embodiment wherein the group II metabotropic glutamate (mGlu) receptor agonist is LY379268.
Finding of prima facie obviousness --- rationale and motivation (See MPEP § 2142-2143)
However, Imre teaches a method of administering LY379268 to rats that serve as an animal model of schizophrenia (abstract). Imre teaches that ketamine, when administered to healthy individuals, produces symptoms common in schizophrenia and has been used in rodents to model behavioral abnormalities associated with schizophrenia, including disruption in the prepulse inhibition of the startle reflex (PPI), working memory deficits and augmented locomotion (page 393, right column, paragraph 2). Imre then teaches that the rats, having the aforementioned schizophrenia symptoms, were injected with LY379268 (page 393, right column, paragraph 3). Also, Imre teaches that LY379268 was shown to have partial effectiveness in the ketamine model of schizophrenia (abstract).
Thus, one of ordinary skill in the art would have been motivated by the general teachings of Downing to include LY379268 as the mGlu receptor agonist as Imre teaches it as a useful compound in treating schizophrenia.
Correspondence
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Anna Grace Kuckla whose telephone number is (703)756-5610. The examiner can normally be reached Monday-Friday 7:30-5.
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/A.G.K./Examiner, Art Unit 1626
/JOSEPH K MCKANE/Supervisory Patent Examiner, Art Unit 1626