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
The amendment filed on 4-27-2026 is acknowledged. Claims 1, 5, 23, 25 and 28 have been amended. Claims 4, 19 and 22 have been canceled. Claims 1-3, 5-7, 10-12, 15, 17-18, 23, 25-26 and 28-29 are pending and currently under examination.
Claim Rejections Maintained
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.
The rejection of claims 1-3, 5-7, 10-12, 15, 17-18, 23, 25-26 and 28-29 under 35 U.S.C. 103 as being obvious over Kong et al. (Pilot and Feasibility Studies 2020;6:20 – IDS filed on 3-17-2025) and Cheng et al. (Journal of Food and Drug Analysis Vol. 27, pages 632-648) is maintained for reasons of record. Cancellation of claims 4, 19 and 22 has rendered the rejection of those claims moot.
Applicant argues:
1. Claims 1, 25, and 28 are amended to recite a specific probiotic bacterial strain: L. plantarum PS128. Claims 1 and 28 are also amended to recite that the combination therapy exhibits a synergistic effect in caregiver-rated Aberrant Behavior Checklist and/or a synergistic increase in one or more of Christensenellaceae, Lachnospiraceae, Blautia, Barnesiella, and Ruminococcaceae. Kong and Cheng, alone or in combination, fail to teach or suggest a method or composition having these features.
2. While Cheng may describe the use of L. plantarum PS128 in certain psychiatric diseases, the reference lacks any teaching or suggestion regarding the combined administration of PS128 and oxytocin.
3. Kong, which lacks any disclosure related to L. plantarum PS128, fails to remedy this deficiency. Instead, Kong provides a clinical trial protocol for assessing the combination of a different probiotic (L. reuteri) and oxytocin. The reference lacks any data demonstrating a synergistic effect conferred by the combined administration of oxytocin and any probiotic, let alone the specific claimed L. plantarum strain.
4. The inventors discovered that the combination of L. plantarum PS 128 and oxytocin conferred a number of advantages over administration of probiotic or oxytocin alone, including improved social and behavioral measurements of ASD, clinical global impression, and gut microbiome interactions.
5. The specification discloses that the combination of PS128 and oxytocin produces a synergistic effect on microbiome composition.
6. A skilled artisan viewing Kong and Cheng would have lacked any basis to derive the claimed subject matter, nor could they have reasonably expected the synergistic and beneficial effects associated with the combination of PS128 and oxytocin.
Applicant’s arguments have been fully considered and deemed non-persuasive.
With regard to Point 1, the ability of the claimed combination therapy to exhibit a synergistic effect in caregiver-rated Aberrant Behavior Checklist and/or a synergistic increase in one or more of Christensenellaceae, Lachnospiraceae, Blautia, Barnesiella, and Ruminococcaceaeis an inherent characteristic of the Lactobacillus plantarum PS128 and oxytocin fusion protein and hence the fusion proteins resulting from the combination of the teachings by Kong et al. and Cheng et al. would have all the immunological characteristics of the instant invention. The mere recognition of inherent properties in the prior art does not render nonobvious an otherwise known invention. In re Wiseman, 201 USPQ 658 (CCPA 1979). Thus, although the prior art does not specifically anticipate the claimed functional interactions, it is the combination of the references that would inherently lead to the modification of the immunological properties. Moreover, the mechanism of action does not have a bearing on the patentability of the invention if the invention was already known or obvious. Granting a patent on the discovery of an unknown but inherent function would remove from the public that which is in the public domain by virtue of its inclusion in, or obviousness from, the prior art. In re Baxter Travenol Labs, 21 USPQ2d 1281 (Fed. Cir. 1991). See M.P.E.P. 2145.
With regard to Point 2, Kong et al. discloses a method of treating a subject diagnosed with or at risk of autism spectrum disorder (ASD) utilizing Lactobacillus reuteri (L. reuteri) and intranasal OXT spray (see abstract) and Cheng et al. disclose the use of Lactobacillus plantarum PS128. Consequently, the use of Lactobacillus plantarum PS128 constitutes an obvious variation of the methods of Kong et al. Moreover, The KSR decision sets forth “if a technique has been used to improve one device, and a person of skill in the art would recognize that it would improve similar devices in the same way, using the technique is obvious unless its actual application is beyond that person’s skill”. Given that Kong et al. discloses the use of the combination of a Lactobacillus species in combination with oxytocin to treat ASD and the of other various Lactobacillus species to treat ASD are well established in the art (as exemplified by Cheng et al., the use of Lactobacillus plantarum PS128 in combination with oxytocin to treat ASD is well within the capabilities of one of ordinary skill in the art. Hence, the requirements of obviousness under the KSR decision are met.
With regard to Points 3-6, contrary to Applicant’s assertion, the specification provides no statistical data supporting the claim of synergy for the full breadth of the claims. Example 1 is limited to a specific regimen and the effect of said regimen to the abundance of Eubacterium hallii. Moreover, while the Example characterized the gut microbiome of in the limited treatment regimen, no statistical data demonstrating synergistic effect in regards to the claimed changes in microbiome species was presented. As set forth in MPEP 716.02(d):
Whether the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the "objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support." In other words, the showing of unexpected results must be reviewed to see if the results occur over the entire claimed range. In re Clemens, 622 F.2d 1029, 1036, 206 USPQ 289, 296 (CCPA 1980) (Claims were directed to a process for removing corrosion at "elevated temperatures" using a certain ion exchange resin (with the exception of claim 8 which recited a temperature in excess of 100C). Appellant demonstrated unexpected results via comparative tests with the prior art ion exchange resin at 110C and 130C. The court affirmed the rejection of claims 1-7 and 9-10 because the term "elevated temperatures" encompassed temperatures as low as 60C where the prior art ion exchange resin was known to perform well. The rejection of claim 8, directed to a temperature in excess of 100C, was reversed.). See also In re Peterson, 315 F.3d 1325, 1329-31, 65 USPQ2d 1379, 1382-85 (Fed. Cir. 2003) (data showing improved alloy strength with the addition of 2% rhenium did not evidence unexpected results for the entire claimed range of about 1-3% rhenium); In re Grasselli, 713 F.2d 731, 741, 218 USPQ 769, 777 (Fed. Cir. 1983) (Claims were directed to certain catalysts containing an alkali metal. Evidence presented to rebut an obviousness rejection compared catalysts containing sodium with the prior art. The court held this evidence insufficient to rebut the prima facie case because experiments limited to sodium were not commensurate in scope with the claims.).
MPEP 716.02(d) further sets forth that to establish unexpected results over a claimed range, applicants should compare a sufficient number of tests both inside and outside the claimed range to show the criticality of the claimed range. In re Hill, 284 F.2d 955, 128 USPQ 197 (CCPA 1960). It should be noted that the specification does not provide any statistical analysis demonstrating the statistical significance of the claim of synergy encompassing the full breadth of the rejected claims.
Additionally, the MPEP states:
716.02(b) Burden on ApplicantBURDEN ON APPLICANT TO ESTABLISH RESULTS ARE UNEXPECTEDAND SIGNIFICANTThe evidence relied up should establish “that the differences in results are in factunexpected and unobvious and of both statistical and practical significance.” Ex parteGelles, 22 USPQ2d 1318, 1319 (Bd. Pat. App. & Inter. 1992) (Mere conclusions inappellants’ brief that the claimed polymer had an unexpectedly increased impact strength“are not entitled to the weight of conclusions accompanying the evidence, either in thespecification or in a declaration.”); Ex parte C, 27 USPQ2d 1492 (Bd. Pat. App. &Inter. 1992) (Applicant alleged unexpected results with regard to the claimed soybeanplant, however there was no basis for judging the practical significance of data withregard to maturity date, flowering date, flower color, or height of the plant.). See also Inre Nolan, 553 F.2d 1261, 1267, 193 USPQ 641, 645 (CCPA 1977) and In re EliLilly, 902 F.2d 943, 14 USPQ2d 1741 (Fed. Cir. 1990) as discussed in MPEP §716.02(c).APPLICANTS HAVE BURDEN OF EXPLAINING PROFFERED DATA“[A]ppellants have the burden of explaining the data in any declaration they proffer asevidence of non-obviousness.” Ex parte Ishizaka, 24 USPQ2d 1621, 1624 (Bd. Pat.App. & Inter. 1992).DIRECT AND INDIRECT COMPARATIVE TESTS ARE PROBATIVE OFNONOBVIOUSNESSEvidence of unexpected properties may be in the form of a direct or indirect comparisonof the claimed invention with the closest prior art which is commensurate in scope with theclaims. See In re Boesch, 617 F.2d 272, 205 USPQ 215 (CCPA 1980) and MPEP §716.02(d) - § 716.02(e). See In re Blondel, 499 F.2d 1311, 1317, 182 USPQ 294,298 (CCPA 1974) and In re Fouche, 439 F.2d 1237, 1241-42, 169 USPQ 429, 433(CCPA 1971) for examples of cases where indirect comparative testing was foundsufficient to rebut a prima facie case of obviousness.The patentability of an intermediate may be established by unexpected properties of anend product “when one of ordinary skill in the art would reasonably ascribe to a claimedintermediate the contributing cause’ for such an unexpectedly superior activity orproperty.” In re Magerlein, 602 F.2d 366, 373, 202 USPQ 473, 479 (CCPA 1979).“In order to establish that the claimed intermediate is a contributing cause’ of theunexpectedly superior activity or property of an end product, an applicant must identifythe cause of the unexpectedly superior activity or property (compared to the prior art) inthe end product and establish a nexus for that cause between the intermediate and the endproduct.” Id. at 479.
Additionally,
716.01(c) Probative Value of Objective EvidenceTO BE OF PROBATIVE VALUE, ANY OBJECTIVE EVIDENCE SHOULDBE SUPPORTED BY ACTUAL PROOFObjective evidence which must be factually supported by an appropriate affidavit ordeclaration to be of probative value includes evidence of unexpected results, commercialsuccess, solution of a long-felt need, inoperability of the prior art, invention before the dateof the reference, and allegations that the author(s) of the prior art derived the disclosedsubject matter from the applicant. See, for example, In re De Blauwe, 736 F.2d 699,705, 222 USPQ 191, 196 (Fed. Cir. 1984) (“It is well settled that unexpected resultsmust be established by factual evidence.” “[A]ppellants have not presented anyexperimental data showing that prior heat-shrinkable articles split. Due to the absence oftests comparing appellant’s heat shrinkable articles with those of the closest prior art, weconclude that appellant’s assertions of unexpected results constitute mere argument.”). Seealso In re Lindner, 457 F.2d 506, 508, 173 USPQ 356, 358 (CCPA 1972); Ex parteGeorge, 21 USPQ2d 1058 (Bd. Pat. App. & Inter. 1991).
ATTORNEY ARGUMENTS CANNOT TAKE THE PLACE OF EVIDENCEThe arguments of counsel cannot take the place of evidence in the record. In re Schulze,346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965). Examples of attorneystatements which are not evidence and which must be supported by an appropriateaffidavit or declaration include statements regarding unexpected results, commercialsuccess, solution of a long-felt need, inoperability of the prior art, invention before thedate of the reference, and allegations that the author(s) of the prior art derived thedisclosed subject matter from the applicant.
Consequently, in the absence of supporting evidence for the claimed genus treatment methods, Applicant’s assertion that the efficacy of any ASD treatment comprising L. plantarum PS128 and oxytocin constitutes an unexpected result is deemed unpersuasive.
With regard to Point 6, the skilled artisan would necessarily know that there would be variability between the effects of individual components and a composition comprising said individual components. Additionally, the skilled artisan would have a reasonable expectation that the combined teachings of Kong et al. and Cheng et al. would have efficacy in treating symptoms of ASD as both references individually teach methods of treating said symptoms and that the treatment compositions arising from the combination of the cited references would necessarily have the same biological and immunological characteristics as treatment compositions of the rejected claims.
As outlined previously, Kong et al. discloses the use of probiotics and oxytocin nasal spray as neuro-social-behavioral treatments for patients with autism spectrum disorders (see abstract).
With regard to claims 1 and 28, Kong et al. discloses a method of treating a subject diagnosed with or at risk of autism spectrum disorder (ASD) utilizing Lactobacillus reuteri (L. reuteri) and intranasal OXT spray (see abstract). Kong et al. differs from the rejected claim in that they don’t explicitly disclose the use of Lactobacillus plantarum PS128. Cheng et al. disclose the use of Lactobacillus plantarum subsp. plantarum PS128 to treat boys aged 7-15 with ASD (see section 5.1 on page 643 and Table 4 on page 642). It would have been obvious to one of ordinary skill in the art at the time of the invention to utilize the Lactobacillus plantarum subsp. plantarum PS128 of Cheng et al. in the methods of Kong et al. as it constitutes a functional equivalent of the probiotic bacteria disclose by Kong et al. One would have had a reasonable expectation of success as both the Lactobacillus plantarum subsp. plantarum PS128 of Cheng et al. and the Lactobacillus reuteri of Kong et al. were shown to have efficacy in treating patients with ASD.
With regard to claims 2-3, Cheng et al. disclose that their treatment outcomes are measured by ABC, SRS, CBCL, CGI-I and SNAP IV (see Table 4).
With regard to claims 5-7, Cheng et al. disclose that the Lactobacillus plantarum subsp. plantarum PS128 is at a concentration of 3 x 1010 CFU/capsule and administered for 28 days (see page 643) and Kong et al. discloses wherein administration comprises multiple doses of the probiotic composition over the course of about I week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 2 months, about 3 months, about 4 months, about 6 months, about 1 year, or as frequently as symptoms dictate (see page 5). Moreover, while Kong et al. do not explicitly disclose that once a day or multiple times a day, it is well established that where 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).
With regard to claim 10, both Kong et al. and Cheng et al. discloses that the probiotic is administered orally (see page 5, left-hand column of Kong et al. for example).
With regard to 11-12, and 17-18, Kong et al. discloses that their treatment methods comprise multiple doses of oxytocin over the course of about 1 week, about 2 weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 2 months, about 3 months, about 4 months, about 6 months, about 1 year, or as frequently as symptoms dictate (see page 5, right-hand column); that the oxytocin is administered once per day (page 5, left-hand column) and that the dosage of oxytocin nasal spray begins with 1 puff of 4 IU daily and after 1 week, the dose will increase to 1 puff per nostril for both nostrils daily (8 IU/rlr1y)).
With regard to claims 23, given that the combination of the cited references results in the use of the same biological components, they would necessarily have the same biological characteristics as those of the rejected claims.
With regard to claim 25, given the combined references disclose the use of both oxytocin and Lactobacillus plantarum subsp. plantarum PS128 it would have been obvious for one of skill in the art to combine them in a single compound.
With regard to claim 26, Cheng et al. disclose the use of probiotic products comprising multiple bacterial strains (in addition to Lactobacillus plantarum subsp. plantarum PS128) in ASD patients (see page 640).
With regard to claim 29, given that the combination of the cited references results in the use of the same biological components, they would necessarily have the same biological characteristics as those of the rejected claims.
Conclusion
No claim is allowed.
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.
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/ROBERT A ZEMAN/Primary Examiner, Art Unit 1645 June 26, 2026
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