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
This application is a US national phase of PCT/EP2020/065620, filed June 5, 2020 with a foreign priority application GB1908154.6, filed June 7, 2019.
Applicant’s amendment filed May 22, 2026 is acknowledged. Claims 3-5, 10-12, 15-20, 23, and 25-31 are canceled, and claim 2 is amended. Currently, claims 1-2, 6-9, 13-14, 21-22, and 24 are pending and under examination.
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.
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.
Claims 1, 6, 9, 13-14, 21-22, and 24 are rejected under 35 U.S.C. 103 as being unpatentable over Jeppsson (WO2019/242839A1, cited in PTO-892 mailed 2/27/2026, hereinafter “Jeppsson”) in view of Steptoe et al. (2007 Brain, Behavior, and Immunity 21:901–912, cited in PTO-892 mailed 2/27/2026, hereinafter “Steptoe”) and Sindhu et al. (04 April 2017, Journal of Diabetes & Metabolic Disorders 16;15:1-8, cited in PTO-892 mailed 2/27/2026, hereinafter “Sindhu”).
Regarding claims 1 and 6, Jeppsson teaches a Lactobacillus plantarum composition comprising strains HEAL 9 (DSM 15312) and/or 299v (DSM 9843) are administered in a human for treating age-related systemic inflammation (abstract, claim 10). Jeppsson teaches either strain is also useful in reducing serum levels of one or more markers of age-related systemic inflammation, such as C-reactive protein (CRP) (pg. 12, lines 12-15). Jeppsson further teaches that age-related low-grade systemic inflammation, also known as ‘inflamm-aging’ is typically characterized by raised levels of C-reactive protein (CRP) and pro-inflammatory cytokines, such as interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-α), and reduced levels of anti-inflammatory cytokines, such as interleukin-10 (IL-10) (p. 1, lines 18-22).
Jeppsson does not teach the human administered HEAL 9 is under acute psychosocial stress.
However, Steptoe teaches acute psychological stress influences circulating inflammatory markers, and these effects may mediate the influence of psychosocial factors on cardiovascular risk and other conditions such as psoriasis and rheumatoid arthritis (abstract). Steptoe teaches several studies showed an elevated level of CRP, as well as other inflammatory markers, in controls with high stress ratings post-task (pg. 904-05, Table 1). Steptoe teaches there is strong animal and in vitro evidence that the autonomic nervous system and neuroendocrine pathways are involved in the stimulation of IL-1b, IL-6, and TNF-α production (pg. 908, col. 1, para 2).
Jeppsson does not teach DSM 15312 reduces elevated soluble fractalkine levels in the plasma.
However, Sindhu teaches fractalkine is involved in the development of numerous inflammatory conditions including metabolic diseases (abstract). Sindhu teaches plasma fractalkine levels were significantly higher in type-2 diabetes (T2D) patients as compared with non-diabetics, as well as positively correlated with inflammatory chemokines/cytokines including IL-6, IL-17A, inter alia (abstract). Sindhu also teaches elevated circulatory fractalkine levels in T2D patients correlated with plasma CRP levels (r=0.65, P=0.02) (pg. 4, col. 2, para 1). Sindhu teaches the data suggest that fractalkine has a broader relationship with important proinflammatory cytokines and it may also have a differential association with these inflammatory proteins in the presence or absence of T2D, indicating a positive association of fractalkine with IL-1β, IL-12p70, and TNF-α (pg. 6, col. 2, para 1).
Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to utilize Jeppsson’s method of administering DSM 15312 to reduce inflammatory cytokine markers such as TNF-α and CRP as an effect of acute psychosocial stress, as suggested by Jeppsson and Steptoe, which would also reduce elevated fractalkine levels that are strongly associated with systemic inflammation (CRP) and other pro-inflammatory cytokines (i.e. TNF-a), as taught by Sindhu. One of ordinary skill in the art would have been motivated to administer DSM 15312 to reduce markers of inflammation and pro-inflammatory cytokines, such as CRP, TNF-α, and fractalkine; and combined with the well-known and general knowledge in the art that acute psychosocial stress induces inflammation as disclosed by Steptoe, there would have been a reasonable expectation of success that the administration of DSM 15312 would reduce levels of pro-inflammatory cytokines, markers of systemic inflammation, as well as elevated levels of fractalkine, caused by acute psychosocial stress.
Regarding claim 9, Jeppsson teaches an effective dose of L. plantarum DSM 15312 (HEAL 9) is from about 106 to about 1014 colony forming units (CFU) per dose, preferably from about 108 to about 1012 CFU per dose, or more preferably from about 109 to about 1011 CFU per dose (claim 7).
Regarding claims 13-14, Jeppsson teaches administration of the invention may include administration is repeated for at least one week, or four weeks, and administered at least once daily (pg. 13, lines 5-14).
Regarding claims 21-22, Jeppsson teaches the probiotic can be diluted in an acceptable diluent, such as water, milk, or other aqueous solvents (i.e. solution) (pg. 7, lines 34-36).
Regarding claim 24, Jeppsson teaches the probiotic composition may be mixed with a liquid or solid carrier before administration, such as food, which meets the limitation of claim 24 (pg. 9, lines 12-24). Therefore, it would have been prima facie obvious to one of ordinary skill in the art to administer the probiotic in the form of food to a human, as taught by Jeppsson.
(New as Necessitated by Amendment) Claim 2 is rejected under 35 U.S.C. 103 as being unpatentable over Jeppsson, Steptoe, and Sindhu as applied to claims 1, 6, 9, 13-14, 21-22, and 24 above, and further in view of Toth et al. (Acta Histochemica 117 (2015) 188–195, hereinafter “Toth”).
As discussed above, Jeppsson teach methods of administering DSM 15312 that reduce markers of systemic inflammation (CRP) and pro-inflammatory cytokines (TNF-Α and IFN-γ), and Steptoe teaches acute psychosocial stress induces inflammation and pro-inflammatory cytokines such as CRP and TNF-α. None of the prior art teaches a method of administering Lactobacillus plantarum DSM 15312 to reduce elevated levels of CD163 resulting from acute psychosocial stress.
However, Toth teaches in influence of flaxseed and/or lactobacilli (Lactobacillus plantarum) inclusion in the diet of piglets from 10 days before to 21 days after weaning, and found the number of CD163-positive cells in the flaxseed + lactobacilli group was significantly lower on the day of weaning (P < 0.05) and 3 days after (P < 0.01). The same effect was observed in the group with lactobacilli alone during the first 3 days after weaning (P < 0.05 and P < 0.01, respectively) and these findings indicate down-regulation of CD163 expression in the jejunal mucosa by lactobacilli (abstract). Toth teaches at weaning, piglets are subjected to many stressful circumstances associated with their change of environment, separation from the mothers, transport, and general replacement of fluid milk nutrition by solid food with a different composition and nutrient value, wherein the complexes of these social, environmental and dietary stresses interfere with gut development and adaptation and are definitely responsible for maldigestion, malabsorption, shift in gut microflora, poor performance and diarrhea in piglets after weaning (PW) (pg. 188, col. 2, para 1). Toth teaches weaning undoubtedly presents a complex of very strong stressful factors for piglets and found the effects (of upregulated CD163) seem to be age-dependent, because the differences between various diet groups 21 days PW were not significant, due probably to the attenuated stress of animals further PW and with more mature intestinal morphology (pg. 194).
Although, Toth does not teach the particular DSM 15312 strain reduces CD163, Jeppsson also teaches Lactobacillus plantarum strains HEAL 9 (DSM 15312) and/or 299v (DSM 9843) are useful in reducing serum levels of one or more markers of age-related inflammation, such as C-reactive protein (CRP), which underlines the species level characteristic of administering L. plantarum probiotic in reducing markers of inflammation (pg. 12, lines 12-15).
Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the time of the effective filing date of the claimed invention to modify the method of administering DSM 15312 to reduce inflammatory cytokine markers such as TNF-α and CRP as an effect of acute psychosocial stress, as taught by Jeppsson and Steptoe, which would also reduce elevated fractalkine levels that are strongly associated with systemic inflammation (CRP) and other pro-inflammatory cytokines (i.e. TNF-a) as taught by Sindhu, and also administer the probiotic in effective dose to further reduce elevated levels of CD163 as taught by Toth with a reasonable expectation of success. Toth teaches that administration of L. plantarum to subjects undergoing the stress associated with weaning downregulates CD163 expression, thereby demonstrating that L. plantarum is capable of modulating CD163 as part of a stress-associated inflammatory response. Thus, one of ordinary skill in the art would have had reason to expect that administration of anti-inflammatory L. plantarum DSM 15312 taught by Jeppsson to a human experiencing acute psychosocial stress would likewise modulate stress-associated inflammatory signaling, including elevated CD163.
Claims 7-8 are rejected under 35 U.S.C. 103 as being unpatentable over Jeppsson, Steptoe, and Sindhu as applied to claims 1, 6, 9, 13-14, 21-22, and 24 above, and further in view of Andersson, et al. (International Journal of Microbiology, 2016; 2016:8469018, pgs. 1-7, cited in PTO-892 mailed 5/6/2024, hereinafter “Andersson”) and Melamed, et al. (Journal of Psychosomatic Research, 1999. Vol. 46, No. 6, pp. 591–598, cited in PTO-892 mailed 5/6/2024, hereinafter “Melamed”).
As discussed above, Jeppsson teach methods of administering DSM 15312 that reduce markers of inflammation (CRP) and pro-inflammatory cytokines (TNF-Α and IFN-γ), and Steptoe teaches acute psychosocial stress induces inflammation and pro-inflammatory cytokines such as TNF-α. None of the prior art teach the method of administering to a human with chronic stress and acute psychosocial stress, nor that the chronic stress is indicated by a score of 3.75 or greater in the Shirom-Melamed Burnout Questionnaire.
However, Andersson teaches a method of administering L. plantarum 299v to a human with acute psychosocial stress and also teaches that chronic stress is related to a sustained increase in secretion of cortisol and that a possible target for probiotics could be chronically stressed individuals (see e.g. page 5, Discussion). Although, Andersson does not explicitly teach the method comprises administering the particular strain DSM 15312, Jeppsson teaches the Lactobacillus plantarum composition comprising strains HEAL 9 (DSM 15312) and/or 299v (DSM 9843) are useful in reducing serum levels of one or more markers of age-related inflammation, such as C-reactive protein (CRP), which underlines the interchangeability of these two strains in reducing markers of inflammation (pg. 12, lines 12-15). Furthermore, Steptoe discloses a study by Bierhaus et al. that elegantly demonstrated that NF-κB in peripheral blood mononuclear cells (PBMC) is rapidly induced during acute stress exposure in parallel with catecholamine and cortisol responses (pg. 908, col. 1, para 2). Andersson further teaches a psychological assessment was included in the study for the test subjects to evaluate their self-perceived stress (pg. 2, sec. 2.2). The assessment was a questionnaire with 30 questions developed by Levenstein, et al. (pg. 2, sec. 2.2).
Melamed also teaches chronic burnout results in elevated salivary cortisol levels (title, abstract). Melamed teaches burnout is known to be associated with occupational stress, and elevated cortisol levels are largely associated with distress and ineffective coping (pg. 591, para 1; pg. 592, para 4). Burnout was measured by the Shirom-Melamed Burnout questionnaire and classified as ‘high’, ‘low’, or ‘high chronic’ burnout, then each group’s cortisol levels were measured (pg. 593-594). Subjects who had a score of 4 on six or more items were considered to display chronic symptoms which meets the limitations of claims 7 and 8 (pg. 593, para 6). Melamed teaches those in the ‘high chronic’ burnout group had significantly higher salivary cortisol levels (pg. 595, para 1).
Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the time of the effective filing date of the claimed invention to modify the method of administering DSM 15312 to reduce inflammatory cytokine markers such as TNF-α and CRP as an effect of acute psychosocial stress, as taught by Jeppsson and Steptoe, which would also reduce elevated fractalkine levels that are strongly associated with systemic inflammation (CRP) and other pro-inflammatory cytokines (i.e. TNF-a) as taught by Sindhu, and also administer the probiotic to humans with chronic stress as well as examination induced stress as taught by Andersson and Melamed with a reasonable expectation of success. One of ordinary skill in the art would have been motivated to do so in light of the disclosure of Andersson that chronically stressed individuals can be a target for probiotic treatment and the expectation that L. plantarum would reduce stress markers, such as cortisol. Since Jeppsson teaches L. plantarum DSM 15312 and 299v are both probiotics that have been used interchangeably for reducing inflammation and decreasing pro-inflammatory cytokines, one of ordinary skill in the art would have a reasonable expectation of substituting one for the other. In addition, one of ordinary skill in the art would have been motivated to administer the L. plantarum DSM 15312 to those with a score of 3.75 or greater on the Shirom-Melamed Burnout questionnaire since they would be considered in need of treatment based on their characterization in the “high chronic” burnout group. Further, it would have been obvious to evaluate the impact of the probiotic’s effects on an individual having chronic stress by including an assessment such as the Shirom-Melamed Burnout questionnaire to classify the study participants before and after probiotic administration.
Response to Arguments
Applicant's arguments filed May 22, 2026 have been fully considered but they are not persuasive.
Regarding Remarks directed to the 35 USC § 103 rejection of claims 1, 6, 9, 13-14, 21-22, and 24, Applicant argues the Office has relied upon hindsight to arrive at a conclusion of obviousness. For example, Sindhu only presents correlative data of an alleged association between fractalkine and certain pro-inflammatory cytokines. Applicant argues Sindhu does not provide any concrete evidence of a functional relationship between fractalkine and pro-inflammatory chemokines and or cytokines. Consequently, the mere fact that Sindhu presents correlative data does not provide a teaching or motivation that would enable a skilled person to conclude that an effect observed with respect to one chemokine or cytokine would necessarily influence fractalkine levels. Applicant points out Sindhu reports that fewer chemokines are correlated with fractalkine in a non-diabetic context. Applicant also argues Sindhu reinforces the notion that the art is unpredictable. In particular, Sindhu indicates that the relationship between certain inflammatory biomarkers, such as IL-6 and fractalkine, differs depending on the clinical context. Applicant argues the specific stress-related biomarkers are also unpredictable to L. plantarum treatment, such as IL-6 in Steptoe, and if Jeppsson provided an expectation of a broad anti-inflammatory effect of DSM 15312, then IL-6 would decrease, whereas the present application saw no effect on IL-6 levels. Applicant argues Jeppsson can not be easily combined with Sindhu and Steptoe, since Jeppsson is in the context of inflammaging and not acute psychosocial stress. Applicant also argues the unpredictability due to wide variability among different L. plantarum strains, that any individual L. plantarum strain would have a desirable effect on reducing elevated level of soluble fractalkine, and Applicant argues the mere fact that certain biomarkers are correlated with fractalkine under only specific conditions cannot be used to supplement the teachings of Jeppsson.
In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971). Jeppsson teaches a method of administering DSM 15312 to reduce inflammation, thereby reducing pro-inflammatory biomarkers. Steptoe teaches acute psychological stress influences circulating inflammatory biomarkers, resulting in elevated CRP levels. Sindhu teaches the link between fractalkine’s relationship in the development of numerous inflammatory conditions and suggests that fractalkine has a broader relationship with important proinflammatory cytokines. Jeppsson teaches administration of DSM 15312 has an anti-inflammatory effect on an individual experiencing inflammation, Steptoe teaches acute psychological stress induces inflammation, and Sindhu teaches fractalkine’s association with pro-inflammatory cytokines, thus one of ordinary skill would have reason to expect fractalkine levels (as well as other pro-inflammatory cytokines) would be reduced when administering DSM 15312 to individuals experiencing acute psychological stress.
Similarly, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). In this case, the suggestion of DSM 15312 as a probiotic that has anti-inflammatory effects at reducing pro-inflammatory cytokines combined with the suggestion of fractalkine associated with pro-inflammatory cytokines, one of ordinary skill in the art would have a reasonable expectation the link would be observed.
Similarly, Jeppsson teaches the L. plantarum strains HEAL 9 and 299v reduce inflammation and efficiently reduce CRP levels in systemic inflammation, which underlines L. plantarum’s ability as a species to reduce inflammation (i.e. lower CRP & TNF-α). Furthermore, the newly applied Toth reference also teaches a different L. plantarum strain and it’s ability to reduce CD163 levels in stressed piglets. Thus, the fact that the inventor has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious. See Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985). As described above in the 103 rejection, Jeppson teaches HEAL 9’s ability to reduce CRP levels, which are correlated with elevated fractalkine levels as taught by Sindhu. It is furthermore generally recognized in the art that stress activates the immune response, which is characterized by the increase in pro-inflammatory cytokines (i.e. TNF-α) as taught by Steptoe, thus it would be reasonable for one of ordinary skill in the art to expect HEAL 9 to reduce markers of inflammation (i.e. CRP, TNF-α, and fractalkine) in stressed individuals, regardless of where or how that stress is induced.
Furthermore, Applicant’s argument about the genetic variability between strains of lactobacilli, does not preclude the presumption for one of ordinary skill in the art to have a reasonable expectation of success that administering a well-known L. plantarum probiotic strain (HEAL 9) would have an anti-inflammatory effect on the individual, regardless of the type of stress that causes such inflammation, thus the claimed method is prima facie obvious over the prior art, especially in view of Jeppsson, Steptoe, and Sindhu.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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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/LOUISE W HUMPHREY/Supervisory Patent Examiner, Art Unit 1657
/JESSICA EDWARDS/
Examiner, Art Unit 1657
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