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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on December 12, 2025 has been entered.
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.
Claims 3-5, 10-12, 15-20, 23, and 25-31 are canceled, and claim 7 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, hereinafter “Jeppsson”) in view of Steptoe et al. (2007 Brain, Behavior, and Immunity 21:901–912, hereinafter “Steptoe”) and Sindhu et al. (04 April 2017, Journal of Diabetes & Metabolic Disorders 16;15:1-8, 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.
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 Andersson, et al. (International Journal of Microbiology, 2016; 2016:8469018, pgs. 1-7, cited in PTO-892 mailed 5/6/2024, hereinafter “Andersson”).
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 DSM 15312 to reduce elevated levels of cortisol.
However, Andersson teaches oral administration of Lactobacillus plantarum 299v reduces cortisol levels in human saliva during examination induced stress which meets the limitation in claim 2 (title). Andersson teaches that there is a connection between the digestive tract and physiological stress and salivary cortisol can be taken as a marker of stress (pg. 1, col. 1, para 1). The study was carried out by administering the test product in a daily dose for two weeks (pg. 2, col. 2, para 1).
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).
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 cortisol as taught by Andersson with a reasonable expectation of success. One of ordinary skill in the art would have been motivated to administer HEAL 9 to reduce cortisol levels, as demonstrated similarly by the administration of 299v, in the method taught by Andersson, as both probiotics are the same species and are used interchangeably for the same purpose (to reduce inflammation), as taught by Jeppsson, Therefore, one of ordinary skill in the art would have understood these two strains of the same species to be equivalent probiotics. Further, the functional effects of administering DSM 15312 in place of the 299v strain in the method taught by Andersson would necessarily result in lowering elevated levels of fractalkine when administered to the same group (humans with psychosocial stress), as this functional property is associated with pro-inflammatory cytokines and systemic inflammation (CRP) as disclosed by Sindhu. As evidenced by the instant specification, biochemical indicators of stress include elevated inflammatory cytokines such as fractalkine, CRP, inter alia, and/or cortisol (pg. 5, lines 30-34) according to the claimed method.
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 and Melamed, et al. (Journal of Psychosomatic Research, 1999. Vol. 46, No. 6, pp. 591–598, previously 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, see pages 4-10, filed December 12, 2025, with respect to the rejection(s) of claim(s) 1-2, 6, 9, 13-14, 21-22, and 24 under USC 103 have been fully considered and are persuasive. Therefore, the rejection has been withdrawn. However, upon further consideration, a new ground(s) of rejection is made in view of Jeppsson, Steptoe, and Sindhu.
Applicant argues in the previous 103 rejection of Andersson in view of Jeppsson, one of skill in the art would have had no motivation to modify Andersson by Jeppsson because the references teach the use of the different probiotic strains (299v and HEAL 9) for treating different health conditions, specifically when considering different downstream consequences between the two conditions (acute psychosocial stress and age related inflammation). Applicant argues the fact that 299v and HEAL9 is interchangeable in a different unrelated condition ARSI that is not APS - as taught in Jeppsson - does not make it any less unpredictable. If 299v does not affect all downstream events (such as IgA), 299v does not affect all downstream events (such as the claimed fractalkine). Swapping 299v with another strain would introduce more, not less, unpredictability.
The Examiner agrees with Applicant that the downstream events of 299v directly affecting cortisol taught by Andersson would not predictably affect the downstream events of lowering fractalkine and/or other pro-inflammatory cytokines taught by Jeppsson. However, Jeppsson teaches both 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, Bauerl et al. (Genes Nutr (2013) 8:165–180) discloses 299v’s ability to downregulate gene expression of TNF receptor superfamily 9, IFN-γ, and IL-17 (abstract, Table 2), which are also positively associated with elevated fractalkine levels as taught by Sindhu (pg. 6, col. 1, para 3).
Applicant argues there is a wide variability among different L. plantarum species, contributing to the presence of genomic lifestyle islands. Such genetic diversity leads to phenotypic diversity among the species, and applicant argues it would be unreasonable to assume that an effect observed in one species will also be present in another species more generally.
In response to applicant's argument that the referenced prior art has not taught the effect of HEAL 9 to lower fractalkine levels as presently claimed, 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 modified 103 rejection, Jeppson teaches HEAL 9’s ability to reduce CRP levels, which are directly 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.
Applicant argues ARS is distinct from APS, and replacing 299v with HEAL 9 for an entirely different unrelated therapeutic purpose is not equivalent or obvious. Applicant argues ARS is a chronic inflammatory condition characterized by long-term elevated cytokines (e.g. CRP) at baseline and reduced immune function, as opposed to APS is an acute stress characterized by short-term high intensity response to a perceived threat, and resolves once the stressor is removed.
In response to applicant’s argument that there is no teaching, suggestion, or motivation to combine the references, 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, Jeppsson teaches HEAL 9 and 299v have immune modulatory effects on individuals suffering from chronic inflammation, which include elevated levels of ‘acute-phase’ proteins such as CRP. Andersson teaches 299v decreases cortisol levels, which is induced with acute psychosocial stress, another marker for activating the immune system. Thus when taken all together, the prior art suggests to one of ordinary skill that utilizing a L. plantarum strain (i.e. 299v, HEAL 9, HEAL 19), would have an immune modulating effect, particularly in reducing its activation, either by reducing pro-inflammatory cytokine expression, enhancing anti-inflammatory cytokine expression, and/or reducing immune activating markers such as cortisol.
Furthermore, Applicant’s submission of support indicating 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
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/LOUISE W HUMPHREY/Supervisory Patent Examiner, Art Unit 1657
/JESSICA EDWARDS/
Examiner, Art Unit 1657