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 .
DETAILED ACTION
Status of the Claims
Claims 1-15 are pending. Claims 1-3 and 10 are the subject of this NON-FINAL Office Action. This is the first action on the merits.
Election/Restrictions
Applicant’s election with traverse of Group I (claims 1-10) and the species of Bmal1 and Per2, prediction of circadian rhythm and athletic performance, and claim 3 in the reply filed on 12/08/2025 is acknowledged. The elections read on claims 1-3 and 10. Applicants argue that “both groups relate to the same overarching inventive concept which is the integration of circadian rhythm based molecular profiling and computational modeling to assess physiological states (including athletic performance) and to guide interventions or applications based on biological timing” and “[t]he distinction between Group I (assessment of circadian rhythm/performance) and Group II (products with RNA protect reagent) is artificial, as the product claims are instrumental to executing the same core method.” This is wrong. The kit of claim 11 is merely a tube comprising “RNA protect reagent.” This is unrelated to the specific method of claim 1/Group I as clearly explained in the Requirement for Restriction/Election. Furthermore, this “RNA protect reagent” is not required in claim 1/Group I. Thus, Applicants arguments are wholly unpersuasive because the groups clearly do not share a special technical feature.
Claims 4-9 and 11-15 are withdrawn.
Note on Data In Spec/Drawings
Much of the data found in the drawings is impossible to decipher due to the use of “gray” and “black” lines, and other drawings which are indistinguishable without color drawings (e.g. Figs. 2, 5 & 24). Other data in which a circadian rhythm is fit onto time course plots of gene expression from saliva samples is not tight. For example, in Figures 23, 25, 30 and 31, many subjects have extremely poor circadian rhythm plots onto time course expression of PER2 and BMAL1.
Claim Rejections - 35 USC § 112- Indefiniteness
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.
Claim 2 is 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 pre-AIA the applicant regards as the invention.
Claim 2 recites a trademarked company name (NanoString™), which completely fails to describe a known good, rather only a source of a good. See MPEP § 2173.05(u) (“It is important to recognize that a trademark or trade name is used to identify a source of goods, and is not the name of the goods themselves. Thus a trademark or trade name does not define or describe the goods associated with the trademark or trade name. . . . If the trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of the 35 U.S.C. 112(b) or pre-AIA 35 U.S.C. 112, second paragraph. . . . The claim scope is uncertain since the trademark or trade name cannot be used properly to describe any particular material or product.”).
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.
Claim(s) 1-3 and 10 is/are rejected under 35 U.S.C. 103 as being unpatentable over NAKGAWA (US20100291553), in view of Winget et al, Circadian rhythms and athletic performance, Med Sci Sports Exerc. 1985 Oct;17(5):498-516, Wolff et al, Exercise Timing and Circadian Rhythms, Curr Opin Physiol. 2019 Apr 27;10:64–69. doi: 10.1016/j.cophys.2019.04.020 and KASAJIMA (US20160206642).
The prior art as a whole demonstrates that it would have been obvious to a skilled artisan at the time of filing to detect Bmal1 and PER2 expression, including in saliva, to determine circadian rhythm abnormalities, which are known to be associated with poor athletic performance with a reasonable expectation of success.
As to claims 1-3 and 10, and detecting and tracking a time course (i.e. three or more time course samples) of BMAL1 and PER2 gene or protein expression to detect circadian rhythms, which is known to affect athletic performance, and using this information to adjust timing of eating, sleeping, exercise, nutrient ingestion and other body adjustments to achieve better health, all of this is incredibly well-known. For example, NAKAGAWA reflects the state of the art: “To cite a familiar example [of defect or diversity in function or gene of a biomolecule involved in a biological clock are causative factors of lifestyle-related diseases], it is known that the mind and body activity and exercise performance also have a circadian rhythm, and a rhythm which maximizes one's own ability, a rhythm which is good for learning or training, an eating rhythm which makes the body weight to increase easily, and the like are considered” (para. 0130). To this end, NAKAGAWA teaches to detect expression variation of BMAL1-CLOCK and PER2 genes at 2.5-hour intervals, or 4-hour intervals using qPCR (paras. 0133-35; see also para. 0137; Figs. 23-24). This allows one to fit the expression levels to a periodic 24-hour cycle to determine circadian rhythm of the subject (id.). In other words, although NAKAGAWA does not explicitly teach assessing and predicting the individual diurnal athletic performance times, both for strength exercises and endurance exercises and then adapting by changing the timing of physical training, recovery, sleep, light exposure, meals timing, or administration of a supplement based on the assessed circadian rhythm and/or predicted diurnal athletic performance times, yet this is strongly suggested by NAKAGAWA, and is incredibly familiar in the circadian rhythm art.
In fact, this suggestion has existed for decades. For example, Winget, in 1985, explained that “[d]aily or circadian rhythmical oscillations occur in several physiological and behavioral functions that contribute to athletic performance. . . . Factors influencing the degree of impairment and duration of readaptation include direction of flight, rhythm synchronizer intensity, dietary constituents and timing of meals, and individual factors such as morningness/eveningness, personality traits, and motivation. It is the intent of the authors to increase awareness of circadian rhythmic influences upon physiology and performance and to provide a scientific data base for the human circadian system so that coaches and athletes can make reasonable decisions to reduce the negative impact of jet-lag and facilitate readaptation following transmeridian travel” (Abstract). More recently, as summarized in Wolff, “the outcomes of exercise may be modified depending on when exercise is performed” (Abstract). Wolff even acknowledges the role of the core molecular clock (which includes BMAL, CLOCK, PER2, etc.) in maintaining circadian rhythms, and its cyclical expression (pgs. 2-3; Fig. 1). Wolff proceeds to explain how this circadian oscillation of the core clock gene expression affects exercise:
Because exercise is a major physiological perturbation, the circadian oscillation of basal physiological rhythms has a direct effect on exercise responses. Several studies in humans and rodents have revealed that variables such as skeletal muscle strength and oxidative capacity demonstrate significant differences over time of day [19–22]. For example, studies have consistently demonstrated increased strength in the later afternoon versus morning [19] while oxidative capacity peaks in the late evening [22]. In addition, basal systemic hormone and metabolite concentrations oscillate over a 24h period, although the impact of these oscillation on exercise are unclear [20,22–25]. It is clear, however, that exercise at different times of day leads to different outcomes [19,25–27]. One recent example was provided by Dalbram and colleagues who reported that exercise in the late active phase of mice reduced the accumulation of body mass during high-fat diet compared to exercise in the early active phase [28]. The effect of circadian timing on an integrative outcome, such as weight gain, is exciting and will provide important considerations for future interventions. Additionally, future studies in both human and rodent interventions must take care to provide transparent reporting of circadian conditions (e.g., light/dark cycles, feeding status), as well as robust time of day sampling rates. Attention to these details are critical to help distinguish intrinsic circadian related changes vs. environmental/behavior effects [29]. We also suggest cautious assessments of experimental circadian controls prior to sweeping conclusions regarding the outcomes of an intervention.
Circadian timing has also been reported to affect exercise outcomes at the molecular level. The molecular responses of muscle to exercise are well-characterized. In particular, the mechanistic target of rapamycin complex 1 (mTORC1) and peroxisome proliferator activated receptor gamma coactivator 1 (PGC1) pathways are widely studied exercise-responsive pathways. Recently, these exercise-stimulated pathways were identified as being downstream of the molecular clock, providing a molecular mechanism through which circadian timing can influence exercise responses [30,31]. For instance, Wu and colleagues reported that PER2 lowers mTORC1 activity [32], and PER2 expression oscillates (peaking at the end of the inactive phase [33]), linking time-of-day to the exercise response. Additionally, morning resistance exercise, but not afternoon exercise in trained individuals lead to the activation of the mTORC1 signaling pathway, as assessed by p70S6K phosphorylation [34]. Despite the influence of circadian timing on hypertrophic signaling following acute resistance exercise, circadian timing of resistance exercise training does not influence skeletal muscle hypertrophy [27,34]. Endurance exercise increases PGC1α, which is a clock-controlled gene in skeletal muscle [35]. Thus, circadian timing may influence the endurance exercise response by modulating the activation PGC1 in skeletal muscle. To our knowledge, no investigations have assessed the impact of circadian timing as a modifier of endurance exercise training responses. However, it is unclear if any human investigation has performed exercise at the onset of the inactive phase (dark), which would closely mirror previous interventions using rodent models [15,36,37].
One approach to test the influence of the circadian clock on exercise outcomes is with genetic models of circadian disruption. In one model of circadian disruption (ClockΔ19), where mice have a 27–28h endogenous period length, mutant mice had a 49% reduction in treadmill exercise duration compared to wild type [38] suggesting that animals with internal clocks out of sync with environmental cues (i.e. misalignment) have reduced exercise capacity. Additionally, in a model of complete circadian disruption, activity levels in mice lacking Bmal1 were severely reduced (~2 fold) compared to wild type animals [39]. Together, these findings suggest that circadian disruption reduces exercise capacity. However, despite reduced exercise capacity in mice with circadian disruption, the animals retain plasticity. Specifically, exercise training restored the exercise capacity of the ClockΔ19 mice, although no studies have examined exercise training in Bmal1 knockout animals. Together, these findings have major therapeutic implications, as circadian disruption has been linked to numerous diseases [24,40,41]. Thus, exercise may reduce mortality through restoring the function of disrupted molecular clocks. Below we highlight the mechanisms through which exercise modulates the molecular clock
(pgs. 3-4). In other words, a skilled artisan would have been familiar with the fact that circadian timing of eating, exercise, sleeping, and ingestion of supplements and other nutrients, as measured by the molecular clock, is important to achieve better health effects. Thus, the prior art is replete with motivation to use circadian rhythm assessment or monitoring via the molecular clock to determine athletic performance, and then adjust eating, exercise, sleeping, and ingestion of supplements and other nutrients to positively effect that performance.
The above prior art does not explicitly teach to use saliva samples.
However, saliva samples were familiar option in the art, regularly used with success to detect gene expression. For example, KASAJIMA teaches that Bmal1 and PER2 can be detected in saliva (para. 0040).
In sum, the prior art demonstrates conclusively that a skilled artisan would have been motivated to detect Bmal1 and PER2 in saliva samples to determine circadian rhythms in subjects, and further determine athletic performance in order to adjust the timing of physical training, recovery, sleep, light exposure, meals timing, or administration of a supplement with a reasonable expectation of success.
The Examiner also notes that he is a skilled artisan in the field of circadian rhythms as demonstrated by the publications found at https://scholar.google.com/citations?user=J47haMEAAAAJ&hl=en. In light of this, the Examiner’s conclusions are also backed by His knowledge in the field.
To put the above another way, a skilled artisan would have expected that both Bmal1 and Per2 expression are cyclical according to circadian rhythms; and that this cyclical nature can be tracked to determine when a subject is at a particular point of a circadian rhythm, or if a rhythm is defective. That skilled artisan would also have known that circadian rhythm timing and defects affect athletic performance, and therefor could make appropriate adjustments. This is all reflected in the fact that Applicants recognize that the prior art teaches that circadian rhythms affect athletic performance (Spec., pgs. 1-5).
What Applicants seem to believe is the invention is the use of non-invasive plasma samples (Spec, pgs. 5-6). However, saliva sample are routinely used in the art. Thus, the Examiner strongly suggests that Applicants provide statistically significant, and low-variability evidence of unexpected results commensurate in scope with the claims. See MPEP § 716.
Double Patenting- Obvious Type
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 obviousness-type 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); and 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 a nonstatutory double patenting ground provided the conflicting application or patent either is shown to be commonly owned with this application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement.
Effective January 1, 1994, a registered attorney or agent of record may sign a terminal disclaimer. A terminal disclaimer signed by the assignee must fully comply with 37 CFR 3.73(b).
Instant claims 1-3 and 10 are rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over conflicting claims 1-20 of US 18/023581, in view of NAKGAWA (US20100291553), Winget et al, Circadian rhythms and athletic performance, Med Sci Sports Exerc. 1985 Oct;17(5):498-516, and Wolff et al, Exercise Timing and Circadian Rhythms, Curr Opin Physiol. 2019 Apr 27;10:64–69. doi: 10.1016/j.cophys.2019.04.020.
The instant claims are obvious over the conflicting claims because the conflicting claims, in light of the prior art above, render the instant claims obvious. More specifically, the conflicting claims teach:
1. A method of assessing circadian rhythm or circadian profile of a subject having cancer and/or assessing a timing of administration of a medicament to said subject having cancer, wherein said method comprises:
Providing at least three samples of saliva, more preferably four samples of saliva, from said subject, wherein said samples have been taken at different time points over the day;
Determining gene expression of the following genes in each of said samples:
a. of at least two members of the core-clock network in each of said samples, in particular of at least two members of the following genes, of the groups comprising ARNTL (BMAL1), ARNTL2, CLOCK, PER1, PER2, PER3, NPAS2, CRY1, CRY2, NR1D1, NR1D2, RORA, RORB, RORC, in particular ARNTL (BMAL1) and PER2, and
b. at least one gene involved in the metabolism of a medicament to be administered to said subject having cancer, including Ces2, and
c. at least one drug target gene that is a target of the medicament to be administered, and
Assessing and predicting by means of a computational step based on said expression levels of said genes over the day the circadian rhythm of said subject and/or assessing a timing of administration of said medicament to said subject, comprising assessing the optimal time of administration of said medicament to said subject and/or assessing the non-optimal time of administration of said medicament to said subject.
Although the conflicting claims fail to teach to predict athletic performance using circadian rhythms, yet NAKGAWA, Winget and Wolff, as explained above, demonstrate that athletic performance, and its modulation was another known predictive function of tracking the molecular clock to track circadian rhythm. In other words, a skilled artisan would have expected, that from tracking the molecular clock and therefore circadian rhythms of a subject, one would easily substitute predicting athletic performance instead of predicting the best timing for medicament administration. And one would do so because athletic performance was a known effect from circadian rhythms just like medicament timing. Finally, a skilled artisan would have used this predictive function of the circadian rhythm to adjust timing of sleep, training, meals, supplements, etc. to achieve maximal training effect as taught in the prior art above. Thus, the conflicting claims render obvious the instant claims.
Prior Art
The following prior art reflects the commonly-understood connection between circadian rhythms and athletic performance: US20110196619 (“It is known that various biological phenomena of living individuals show a “periodical rhythm” that autonomously oscillates. This periodical rhythm is called a “biological rhythm”. In particular, it is known that a “circadian rhythm” whose period is about one day widely controls biological phenomena such as a sleep/wake cycle, body temperature, blood pressure, and a diurnal variation in hormone secretion. Furthermore, a circadian rhythm is involved in the activity of mind and body, athletic ability, and the sensitivity to drugs.”; “Moreover, in more familiar cases, by utilizing the circadian rhythm of the activity of mind and body and athletic ability, the activity time that maximizes one's ability in learning and training and the ingestion time that does not easily cause a gain in weight (or easily causes a gain in weight) have started to be examined.”).
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Aaron Priest whose telephone number is (571)270-1095. The examiner can normally be reached 8am-6pm.
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/AARON A PRIEST/Primary Examiner, Art Unit 1681