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
Claims 2-3 and 8-10 are canceled. Claims 1, and 4-7 are pending and under consideration in this office action.
Priority
The claims are entitled to an effective filing date of February 1, 2019.
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.
(Maintained) Claims 1 and 4-7 remain rejected under 35 U.S.C. 103 as being unpatentable over Liu (Brain research, 2016, 1631, 1-12) in view of Tsai (EP 2937424; as previously relied upon), with evidence from Pinto (Journal of Neural Transmission, 2016, 123(8), 991-1000.
Regarding claim 1, Liu teaches producing early life stress (ELS) mice with multiple deficits including abnormal behaviors, hypothalamus–pituitary–adrenal axis (HPA) dysregulation, immune alterations and changes in neurochemicals in the prefrontal cortex. See the first passage on page 8. Liu teaches administering Lactobacillus plantarum PS128 (PS128) by gavage for 4 weeks to mice (e.g. non-human animals) assigned to an ELS experimental group (ELS+PS128) and to a separate naïve experimental group. Liu teaches giving the ELS and naïve experimental groups saline (e.g. carrier) re-suspended PS128 daily at 109 CFU/mouse/day. See sections 4.3-4.3. Liu suggests that it is possible that PS128 normalizes the maternal separation (MS)- induced dysregulation of the HPA axis via modulating the gut microbiota. See the left column on page 8.
Evidentiary reference Pinto discloses that attention-deficit/hyperactivity disorder (ADHD) has been linked to dysregulation of the HPA axis. See the abstract of Pinto. Thus, Liu inherently teaches ELS mice in need of a treatment for hyperactivity because the ELS mice of Liu have HPA dysregulation, and HPA dysregulation is linked to a hyperactivity disorder as evidenced by Pinto.
Liu is silent regarding the accession number of the PS128. As such, Liu does not teach L. plantarum subsp. plantarum PS128, which is deposited under DMZ accession No. DSM 28632
Tsai teaches Lactobacillus plantarum subsp. plantarum PS 128 deposited under DSMZ Accession No. DSM 28632. See claim 1. Tsai teaches a method for preventing or treating a stress-induced disorder or a psychiatric disorder comprising administering L. plantarum PS128. See [0016] and claim 3. Tsai, in example 3, teaches administering PS128 to mice at a concentration of 109 CFU in 0.2 mL saline/mouse/day for 4 weeks. See [0037]. Tsai suggests that the mice underwent early life stress (ELS). See [0036]. Thus, Tsai teaches administering the PS128, deposited under DSMZ Accession No. DSM 28632, to mice.
It would have been obvious to a person of ordinary skill in the art prior to the effective filing date of the instantly claimed invention to replace the PS128 of Liu with the PS128 (DSM 28632) of Tsai because one would reasonably expect the strains to be identical. There would be a reasonable expectation of success because Liu and Tsai demonstrate administering PS128 to mice with ELS.
Regarding claims 4 and 7, Liu teaches administering PS128 to mice by gavage daily for 4 weeks. See sections 4.3-4.3.
Tsai, in example 3, teaches administering PS128 to mice for 4 weeks. See [0037].
Thus, Liu and Tsai teach administering PS128 to a mouse non-human animal (relevant to instant claim 2) for at least one week (relevant to instant claim 7).
Regarding claim 5, Liu teaches administering PS128 (109 CFU/mouse/day ) by gavage to an ELS experimental group. See section 4.4.
Tsai, in example 3, teaches administering PS128 at a concentration of 109 CFU in 0.2 mL saline/mouse/day for 4 weeks. See [0037]. Tsai teaches an oral administration of PS128. See [0052] and claim 15.
Regarding claim 6, Tsai teaches preparing a PS128 and excipient powder containing 1x1011 CFU per gram of powder. Then, the PS128 powder is dissolved into 5x109 CFU/mL saline solution before animal treatment [0050]. For the animal treatment, Tsai teaches administering to 109 CFU in 0.2 mL saline/mouse/day to rats weighing 220-330g (i.e. 0.22kg -0.33kg) [0051][0052]. Thus, suggests a dose between 0.03g/kg body weight/day to 0.045g/kg body weight/day because (1) there are 0.05g PS128 powder in every mL (i.e. 1x1011 CFU/g * 0.05g = 5x109 CFU), (2) Tsai suggests 0.01g PS128 powder are administered to rats weighing 0.22-0.33kg (0.05g/mL *0.2mL=0.01g), and (3) 0.01g PS128 divided by 0.22-0.33kg equals 0.03g/kg body weight/day to 0.045g/kg body weight/day.
Response to Arguments
Applicant's arguments filed 11/05/2025 have been fully considered, but they are not persuasive.
§103 rejection of claims 1 and 4-7 over Liu in view of Tsai with evidence from Pinto
Applicant argues that the allegation that “Liu inherently teaches ELS mice in need of a treatment for hyperactivity” is speculative, and that the Examiner improperly assumes causation and reciprocity between HPA dysregulation and ADHD. See the paragraph spanning pages 2-3.
This argument is not persuasive because it is not commensurate in scope with the instant claims. Under the broadest reasonable interpretation, the term “hyperactivity” in independent claim 1 encompasses all forms of hyperactivity. The specification does not provide an alternative definition for the term. Liu states that “[t]he affected animals [of early life stress (ELS)] show long-lasting behavioral and physiological phenotypes, including…HPA axis hyperactivity, and abnormal neurochemical changes”. See the last passage in the left column on page 2. Furthermore, Liu teaches finding that “PS128 significantly reduced the hyperactive HPA axis response and depression-like behaviors in ELS mice”. See the last full paragraph on page 8. Thus, Liu teaches treating a form of hyperactivity. Pinto is merely relied upon for evidence that HPA dysregulation has been linked with ADHD.
Applicant argues that the corticosterone measured in Liu and the cortisol reported in Pinto are indexes of HPA axis activity for mice and human respectively. See the second paragraph on page 3 of the remarks. Applicant argues that Liu involves up-regulation of corticosterone levels and HPA axis hyperactivity, and further discloses that administration of PS128 reduces serum corticosterone levels in ELS mice and normalizes ELS-induced HPA axis hyperactivity. In contrast, Pinto explicitly points out that ADHD is associated with reduced cortisol level and blunted cortisol activity. Therefore, the physiological mechanisms taught in Liu and Pinto are contradictory to each other and no reasonable correlation can be drawn between the two references. See the paragraph spanning pages 3-4 of the remarks.
This argument is not persuasive because evidentiary reference Pinto is merely relied upon for teaching the known link between ADHD and the dysregulation of the hypothalamic-pituitary-adrenal axis. Pinto is not relied upon for teaching the claimed hyperactivity element. Rather, Liu is relied upon for teaching that element because Liu teaches the hyperactivity of the HPA axis.
Applicant argues that it is well established in the art that HPA axis dysregulation may manifest in different forms, including hyperactiviation, hypoactivation or a mixed state thereof. Applicant asserts that after reviewing Liu and Pinto, a person of ordinary skill in the art should understand that Liu intends to reduce the corticosterone level and normalized hyperactivation of the HPA axis, whereas Pinto links ADHD to down-regulation of cortisol level and blunted HPA axis activity, which is widely recognized in the art as indicative of a hypoactive HPA response. Applicant asserts that a person of ordinary skill in the art would not regard the subjects of Liu as being in need of treatment for hyperactivity. Applicant asserts that Examiner’s proposed combination is therefore premised on a misinterpretation of the underlying technical facts. See the first paragraph on page 4 of the remarks.
This argument is not persuasive because arguments of counsel cannot take the place of factually supported objective evidence (MPEP 2145 or 716.01(c)). See, e.g., In re Huang, 100 F.3d 135, 139-40, 40 USPQ2d 1685, 1689 (Fed. Cir. 1996); In re De Blauwe, 736 F.2d 699, 705, 222 USPQ 191, 196 (Fed. Cir. 1984). There is no evidence of record indicating that the HPA axis hyperactivity taught by Liu is not a form of hyperactivity, as indicated by Applicant. In other words, Applicant asserts that HPA axis dysregulation may manifest as hypoactivation. However, Liu is relied upon for explicitly teaching “HPA axis hyperactivity”. See, for example, the last line of page 8 of Liu. Therefore, it is unclear, based on Applicant’s argument, how the evidence of Pinto contradicts that explicit teaching of Liu. Moreover, the rejection above is based on the combination of Liu and Tsai with evidence from Pinto; it is not based on Liu and Pinto, as indicated by Applicant. Applicant points out that a person of ordinary skill in the art should understand that Liu intends to normalize hyperactivation of the HPA axis. Applicant has not pointed to a claimed element that differentiates the claimed hyperactivity from the HPA axis hyperactivity taught by Liu.
Applicant asserts that there is no reasonable motivation to refer to Pinto in view of Liu since Liu never mentions ADHD and Pinto fails to disclose treating ADHD with probiotics. Even if Liu and Pinto could be combined a person of ordinary skill in the art would still have no basis to conclude that the PS128 of Liu would be therapeutically effective for the ADHD condition described in Pinto. See the last paragraph on page 4 of the remarks.
This argument is not persuasive because, as set forth above, the rejection is not based on the combination of Liu and Pinto, rather the rejection is based on the combination of Liu and Tsai, with evidence from Pinto. Every claimed element is taught by the combination of Liu and Tsai.
Applicant argues that the stress-induced disorder or psychiatric disorder disclosed in Tsai is different from the specific abnormal emotion or behavior claimed in the present application. Therefore, Tsai fails to cure the deficiencies of Liu and Pinto. See the first paragraph on page 5 of the remarks.
This argument is not persuasive because Tsai is not relied upon for teaching the claimed abnormal emotion or behavior. Rather, Liu is relied upon for teaching that element. Tsai is relied upon for teaching L. plantarum PS128 deposited under DSM 28632. Thus, the argument is unpersuasive because every claimed element is taught by the combination of Liu and Tsai.
Conclusion
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KIMBERLY C BREEN whose telephone number is (571)272-0980. The examiner can normally be reached M-Th 7:30-4:30, F 8:30-1:30 (EDT/EST).
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/K.C.B./Examiner, Art Unit 1657
/LOUISE W HUMPHREY/Supervisory Patent Examiner, Art Unit 1657