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 .
Election/Restrictions
Applicant’s election of the entire grouping of species, rather than a single species from each grouping, in the reply filed on 10 September 2025 is acknowledged. When the entire grouping is elected Applicant is admitting on the record that this is “a single grouping of patentably indistinct species” as stated in the previous action. Thus, the CSF1 inhibitors are obvious variants of one another. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Applicant indicates Claim 4 is withdrawn.
Claims 1-3 and 5-22 are examined upon their merits.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. This application claims the benefit of US Provisional Application Nos. 63/381,855 filed on 1 November 2022 and 63/288,046 filed on 10 December 2021.
Therefore, Claims 1-3 and 5-22 have an effective US filing date of 10 December 2021.
Information Disclosure Statement
The information disclosure statements (IDSs) submitted 1 May 2023 through 10 September 2025 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 § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1 and 15 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
The term “increasing” in claims 1 and 16 is a relative term which renders the claims indefinite. The term “increasing” is not defined by the claims, nor does the specification provide a standard for ascertaining the requisite degree. Additionally, there are no active method steps whereby an increase in phase locking of neurons to gamma oscillations in at least one brain region of the subject is assessed. Therefore, it is unclear if assessing an increase in phase locking in at least one brain region is required for infringement of the invention. Thus, one of ordinary skill in the art would not be reasonably apprised of the scope of the invention of Claims 1 and 16. For purposes of applying prior art, the claim will be interpreted as requiring: administering an inhibitor including a colony-stimulating factor-1 receptor (CSF1R) inhibitor or a colony-stimulating factor-1 (CSF1) inhibitor to the subject; and administering a stimulus to the subject having a frequency from about 20 Hz to about 60 Hz. The increased phase locking in at least one brain region, and treating Alzheimer’s disease, are interpreted as inherent effects that occur subsequent to these active administering steps. This affects the scope of all depending claims.
Claim 15 is indefinite wherein it recites the subject has at least one Apolipoprotein E4 (APOE4) allele, yet there are no positively stated active steps for assessing the subject’s allele. For purposes of applying prior art, this claim will be interpreted as not requiring an assessment of APOE4 allele, but is merely an inherent feature of the subject in need of Alzheimer's disease treatment of Claim 1.
Claims 14 and 20 are indefinite because it is unclear if assessing an increase in phase locking in the visual cortex or the hippocampus is required for infringement of the invention of the claims. For purposes of applying prior art, these claims will be interpreted as not requiring assessing an increase, and these claims will be anticipated by the active administering steps of Claims 1 and 16.
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.
Claims 1-3 and 5-22 are rejected under 35 U.S.C. 103 as being unpatentable over Alzheimer’s Drug Discovery Foundation, CognitiveVitality.org, published 21 December 2018 (hereafter “AD Foundation” reference) and Martorell et al., Cell, 177(2):256-271, Epub 2019 Mar 14 (hereafter “Martorell”).
Regarding claim 1, the AD Foundation reference discloses pexidartinib is a selective inhibitor of the colony-stimulating factor 1 receptor (CSF-1R), thus teaching the CSF1 inhibitor of the instant claim. The reference discloses, “Cognitive enhancing benefits have been demonstrated for CSF-1 and CSF-1R inhibitors in art accepted animal models of Alzheimer’s disease (AD) (paragraph bridging pages 3-4). Specifically, administration of pexidartinib (a.k.a. PLX3397) “offered minor cognitive benefits on some memory tasks, and reduced microglial association with plaques”. The reference further discloses Phase 2a clinical trials of pexidartinib for mild to moderate Alzheimer’s disease (pg. 9, last paragraph).
Regarding claims 2 and 3, the AD Foundation reference discloses the pexidartinib of instant claims 2 and 3.
Regarding claim 15, since there is no active step for assessing APOE4 allele and this is interpreted as an inherent feature of the subject of Claims 1 and 16. The AD Foundation teaches human clinical trials with pexidartinib for the treatment of AD.
The AD Foundation reference is silent with respect to the step of administering a stimulus to the subject having a frequency from about 20 Hz to about 60 Hz, as recited by independent claims 1 and 16; the about 40 Hz stimulus of instant claims 5, 17 and 22; the administration regimens recited by instant claims 6-13 and claims 18-19; and the device of instant claim 21. The Martorell reference, however, remedies these deficiencies.
Regarding claims 1 and 16, the Martorell et al. teaches administering an auditory tone stimulus that drives gamma frequency neural activity in the auditory cortex and hippocampus (pg. 2, Summary). The Graphical Abstract on page 2 of Martorell indicates the stimulus is at 40 Hz, which teaches a stimulus having a frequency from about 20 Hz to about 60 Hz, as claimed.
Regarding claims 5, 17 and 22, Martorell et al. discloses a stimulus of 40 Hz (see Figure 1 and legend), which teaches the limitation recited by each of these claims.
Regarding claims 12, 13 and 19, Figure 3 and legend of the Martorell reference teaches stimulus administered non-invasively for 1 hr/day, which teaches the limitation of “at least one hour per day” required by these claims.
Regarding claims 14 and 20, Martorell discloses an auditory tone stimulation that drove gamma frequency neural activity in the hippocampal CA1 (pg. 2, Summary), therefore teaching gamma oscillations to at least one brain region, namely, the hippocampus, as claimed.
Regarding claim 21, the Martorell prior art teaches speakers provide a tone at 40 Hz (pg. 15, last paragraph), which teaches “providing a device that administers a stimulus…wherein the stimulus has a frequency of from about 20 Hz to about 60 Hz” as claimed.
While the Martorell prior art reference discloses co-administration of the auditory stimulus with another treatment (namely, a visual stimulus) it is silent with respect to the administration of a CSF1 inhibitor or the specific CSF1R inhibitor of the claims – pexidartinib.
It would have been obvious to a person having ordinary skill in the art, before the effective filing date of the application, to combine the pexidartinib treatment, as taught by the AD Foundation reference, with the auditory stimulus, as taught by Martorell. The court has held that it is obvious to combine two elements each of which is taught by the prior art to be useful for the same purpose. No specific teaching or suggestion is needed for this combination since the idea of combining them flows logically from their having been individually taught in the prior art as useful for the same purpose. See In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980). MPEP 2144.06. Such is the case here, where pexidartinib is disclosed as having cognitive enhancing benefits in art accepted animal models of Alzheimer’s disease (AD) (paragraph bridging pages 3-4), enough to warrant human clinical trials; and, Martorell discloses “Seven days of auditory GENUS improved spatial and recognition memory and reduced amyloid in AC and hippocampus of 5XFAD mice” (pg. 2, Summary). Therefore, it is prima facie obvious to combine these elements for the treatment of AD, and no teaching, suggestion or motivation is required for this combination, since each element is disclosed as useful for treating AD.
The Martorell prior art differs from the claimed invention only with respect to the specific regimen for administering the stimulus. Martorell discloses administering the stimulus for 7 days (Figure 3 legend) but the instant claim recite 30 days (claims 9, 11, and 18); or stipulate that the CSF1 inhibitor be administered prior to the stimulus (claim 6) or 20 days prior (claim 7). The Court has stated that, generally, such differences amount to mere optimization and will not support patentability unless there is evidence indicating the claimed feature 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). (Claimed process which was performed at a temperature between 40°C and 80°C and an acid concentration between 25% and 70% was held to be prima facie obvious over a reference process which differed from the claims only in that the reference process was performed at a temperature of 100°C and an acid concentration of 10%.); see also Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 (“The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages.”); In re Hoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969) (Claimed elastomeric polyurethanes which fell within the broad scope of the references were held to be unpatentable thereover because, among other reasons, there was no evidence of the criticality of the claimed ranges of molecular weight or molar proportions.). For more recent cases applying this principle, see Merck & Co. Inc. v. Biocraft Laboratories Inc., 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir.), cert. denied, 493 U.S. 975 (1989); In re Kulling, 897 F.2d 1147, 14 USPQ2d 1056 (Fed. Cir. 1990); and In re Geisler, 116 F.3d 1465, 43 USPQ2d 1362 (Fed. Cir. 1997). In KSR International Co. v. Teleflex Inc., 550 U.S. 398 (2007), the Supreme Court held that "obvious to try" was a valid rationale for an obviousness finding, for example, when there is a "design need" or "market demand" and there are a "finite number" of solutions. 550 U.S. at 421.
Further, MPEP 2144 sets forth Applicant' s burden for rebuttal of a prima facie case of obviousness based upon routine optimization. Applicant must provide either a showing that the particular amount or range recited within the claims is critical; and/or a showing that the prior art reference teaches away from the claimed amount. In the instant case, the specification as filed provides no evidence that the particular amount or range recited within the claims is critical because the specification does not demonstrate criticality. Regarding the timing of administration with respect to the CSF1 inhibitor and stimulus, the specification states: “In some cases, the inhibitor can be administered prior to the administration of the stimulus such as, for example, one day before, two days before, a week before, 10 days before, 20 days before, 25 days, 40days, 50 days, or more before, including all values and sub-ranges in between. In some cases, the inhibitor can then continue to be administered concurrently with the administration of the stimulus. In other cases, the administration of the inhibitor is stopped prior administration of the stimulus” (paragraph [00268]). Therefore, the interval between administration steps does not appear to be critical for the invention. Regarding the duration of the administration of the stimulus, the specification discloses a range of days: from 20 days (paragraph 00283]) to three weeks (paragraph [00273]); 21 days (paragraph [00220]); 42 days (paragraph [00288]); and 50 days (paragraph [00194]). Therefore, there appears to be no criticality to the duration of the administering step of the invention.
For all of these reasons, the invention of claims 1-3 and 5-22 is obvious in view of the combined teachings of the prior art.
Double Patenting
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 1-3 and 5-22 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-16 of U.S. Patent No. 12,434,072 in view of the AD Foundation reference (cited above). The reference (patented) claims are directed to a method for treating mild cognitive impairment or Alzheimer's disease comprising administering to the subject a visual stimulus that is emitted at a 40 Hertz (Hz) frequency, thereby slowing a progression of mild cognitive impairment or Alzheimer's disease. The reference does not disclose co-administering an inhibitor of CSF1 along with the stimulus. However, the AD Foundation reference remedies this deficiency by disclosing pexidartinib is a selective inhibitor of the colony-stimulating factor 1 receptor (CSF-1R) that “offered minor cognitive benefits on some memory tasks, and reduced microglial association with plaques”. As stated above, the court has held that it is obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose. No specific teaching or suggestion is needed for combination – the idea of combining them flows logically from their having been individually taught in the prior art as useful for the same purpose. See In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980).
Claims 1-3 and 5-22 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-51 of U.S. Patent No. 12,311,194 in view of the AD Foundation reference. The patented claims are directed to a method for treating dementia or Alzheimer's disease in a subject in need thereof, the method comprising: delivering an auditory stimulus and visual stimulus having a frequency of about 20 Hz to about 60 Hz to the subject, wherein the visual stimulus and the auditory stimulus are synchronized. The reference patent does not disclose co-administering an inhibitor of CSF1 along with the stimulus. However, the AD Foundation reference remedies this deficiency by disclosing pexidartinib is a selective inhibitor of the colony-stimulating factor 1 receptor (CSF-1R) that “offered minor cognitive benefits on some memory tasks, and reduced microglial association with plaques”. As stated above, the court has held that it is obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose. No specific teaching or suggestion is needed for combination – the idea of combining them flows logically from their having been individually taught in the prior art as useful for the same purpose. See In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980).
Claims 1-3 and 5-22 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-65 of U.S. Patent No. 12,296,106 in view of the AD Foundation reference. The patented claims are directed to a method to improve cognitive function comprising administering to the subject a non-invasive stimulus having a frequency of about 35 Hz to about 45 Hz. The reference patent does not disclose co-administering an inhibitor of CSF1 along with the stimulus. However, the AD Foundation reference remedies this deficiency by disclosing pexidartinib is a selective inhibitor of the colony-stimulating factor 1 receptor (CSF-1R) that “offered minor cognitive benefits on some memory tasks, and reduced microglial association with plaques”. As stated above, the court has held that it is obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose. No specific teaching or suggestion is needed for combination – the idea of combining them flows logically from their having been individually taught in the prior art as useful for the same purpose. See In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980).
Claims 1-3 and 5-22 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-22 of U.S. Patent No. 12,318,549 in view of the AD Foundation reference. The patented claims are directed to a method comprising stimulating a subject with a plurality of light pulses at a pulse frequency of about 35 pulses/s to about 45 pulses/s, which is equivalent to 35 to 45 Hz. The patented method recites an inherent result of reducing tau phosphorylation in the subject, however, there is no method step whereby this effect is assessed. Tau hyperphosphorylation is a characteristic feature of Alzheimer’s disease pathology. Thus, the patented method reads upon administering a stimulus 35-45 Hz with an inherent effect of “treating Alzheimer’s disease”. The reference patent does not disclose co-administering an inhibitor of CSF1 along with the stimulus. However, the AD Foundation reference remedies this deficiency by disclosing pexidartinib is a selective inhibitor of the colony-stimulating factor 1 receptor (CSF-1R) that “offered minor cognitive benefits on some memory tasks, and reduced microglial association with plaques”. As stated above, the court has held that it is obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose. No specific teaching or suggestion is needed for combination – the idea of combining them flows logically from their having been individually taught in the prior art as useful for the same purpose. See In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980).
Conclusion
No claim is allowed.
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/STACEY N MACFARLANE/ Examiner, Art Unit 1675