DETAILED ACTION
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 8/19/2025 has been entered.
Status of Claims
Currently, claims 25-44 are pending in the instant application. Claims 25-33, 35, 39, and 43-44 are withdrawn from consideration as being drawn to non-elected inventions. Claims 34, 36-38, and 40-42 are currently under examination. All the amendments and arguments have been thoroughly reviewed but are deemed insufficient to place this application in condition for allowance. The following rejections constitute the complete set being presently applied to the instant Application. This action is NON-FINAL.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Any rejection not reiterated is hereby withdrawn in view of the amendments to the claims.
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
Written Description
Claims 34, 36, 37, 38, and 40-41 are rejected under 35 U.S.C. 112(a) as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, at the time the application was filed, had possession of the claimed invention.
Relevant to the lack of particular structural limitations in the rejected claims drawn to methods of treating any disease associated with increased levels of circulating succinate with any probiotic product, MPEP 2163 states:
The claimed invention as a whole may not be adequately described if the claims require an essential or critical feature which is not adequately described in the specification and which is not conventional in the art or known to one of ordinary skill in the art.
Additionally, at 2163IIA3(a), the MPEP states:
“…describing a composition by its function alone typically will not suffice to sufficiently describe the composition. See Eli Lilly, 119 F.3 at 1568, 43 USPQ2d at 1406 (Holding that description of a gene’s function will not enable claims to the gene “because it is only an indication of what the gene does, rather than what it is.”); see also Fiers, 984 F.2d at 1169-71, 25 USPQ2d at 1605-06 (discussing Amgen Inc. v. Chugai Pharm. Co., 927 F.2d 1200, 18 USPQ2d 1016 (Fed. Cir. 1991)). An adequate written description of a chemical invention also requires a precise definition, such as by structure, formula, chemical name, or physical properties, and not merely a wish or plan for obtaining the chemical invention claimed. See, e.g., Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 927, 69 USPQ2d 1886, 1894-95 (Fed. Cir. 2004) (The patent at issue claimed a method of selectively inhibiting PGHS-2 activity by administering a non-steroidal compound that selectively inhibits activity of the PGHS-2 gene product, however the patent did not disclose any compounds that can be used in the claimed methods. While there was a description of assays for screening compounds to identify those that inhibit the expression or activity of the PGHS-2 gene product, there was no disclosure of which peptides, polynucleotides, and small organic molecules selectively inhibit PGHS-2. The court held that “[w]ithout such disclosure, the claimed methods cannot be said to have been described.”).
The claimed elected invention is broadly directed to methods for treatment of and/or prevention of any disease “associated” with increased levels of circulating succinate in a patient comprising administering any probiotic product (including any Odoribacter spp, Clostridium spp, Phascolarctobacterium spp, Ruminococcus spp, and combinations thereof) to the patient who has had the presence of succinate, in a biofluid sample from the patient, detected above a predetermined threshold level. The claims require that the probiotic product functionally decreases the ratio of succinate producing bacteria to succinate consuming bacteria [claim 38 specifies the ratio as: (Prevotellaceae + Veillonellaceae) / (Odoribacteriaceae + Clostridiaceae); (P+V)/(O+C)] in the intestinal tract of the patient and/or decreases the levels of circulating succinate of the patient, as well as treats or prevents any disease associated with increased levels of circulating succinate. Dependent claims require the patient is obese (claim 36) or has a disease selected from the group consisting of obesity, cardiovascular disease, hypertension, type 2 diabetes mellitus, chronic heart failure, ischemic heart disease, ischemia/reperfusion injury, and diabetic nephropathy (claim 37).
In the case of the instant claims, identifying probiotic products that function to decrease the ratio of succinate producing bacteria to succinate consuming bacteria [claim 38 specifies the ratio as: (Prevotellaceae + Veillonellaceae) / (Odoribacteriaceae + Clostridiaceae); (P+V)/(O+C)] in the intestinal tract of the patient and/or decreases the levels of circulating succinate of the patient, as well as treat or prevent any disease associated with increased levels of circulating succinate is a critical feature of the claimed methods.
With regard to circulating succinate levels, obesity, and gut microbiota, the specification teaches:
in a cohort of 91 patients stratified according to obesity and T2DM, plasma succinate levels were significantly higher in obese than lean individuals. The specification teaches that a multiple regression model adjusted for age and gender showed that BMI and glucose were the main determinants of circulating succinate levels (page 54, lines 10-20).
The specification teaches that 16S rRNA gene sequencing revealed that in a second independent cohort of twenty subjects, Firmicutes/Bacteroidetes ratio in obese subjects was increased, while there was a decrease in richness and biodiversity at the phylum and genus level (figures 5B-C, page 55, lines 20-32). The specification teaches there was an increase in some succinate producing (Prevotellaceae and Veillonellaceae) bacteria and a decrease in some succinate consuming (Odoribacteraceae and Clostridaceae) bacteria in obese vs non obese individuals (page 56).
The specification teaches whole genome shotgun sequencing in a third cohort of 17 subjects revealed an increase in Veillonellaceae correlated with circulating succinate levels in obese vs lean individuals (page 57).
The specification teaches a fourth cohort of 9 obese subjects were assessed for succinate levels following a dietary weight loss intervention (page 58). The specification teaches that serum succinate levels decreased as did succinate producing bacteria Prevotellaceae and Veillonellaceae. The specification teaches a correlation between circulating succinate levels and (P+V)/(O+C).
The specification teaches that a cohort of 19 subjects were counseled on healthy habits and studied at baseline and 2 years thereafter. The specification teaches no significant differences in body weight were observed. The specification teaches that at the end of the 2 year follow-up, an increase in the (P+V)/(O+C) ratio was associated with increased in succinate levels in some subjects while a decrease in the ratio was associated with a decrease in succinate levels. However, since no significant body weight differences were found in the patients, the effect of this ratio and the effect of succinate levels on the health of this patient population is unclear.
With regard to the actual administration of a probiotic, the specification teaches that C57/B16 obese mice were treated with Odoribacter laneus with 100 uL bacteria at 1/109CFU/mL. The specification teaches that glucose tolerance increased in the Odoribacter laneus treated animals. However the specification does not teach whether circulating succinate levels were decreased, or whether the ratio of succinate producing bacteria to succinate consuming bacteria was decreased in Odoribacter laneus treated animals. The specification does not teach the composition of any probiotic products that decrease the levels of circulating succinate in subjects, or which decrease the ratio of succinate producing bacteria to succinate consuming bacteria, in subjects. The specification does not teach the composition of any probiotic that can treat or prevent obesity, cardiovascular disease, hypertension, type 2 diabetes mellitus, chronic heart failure, ischemic heart disease, ischemia/reperfusion injury, or diabetic nephropathy.
While the skilled artisan may be capable of making probiotic products, possession may not be shown by merely describing how to obtain possession of members of the claimed genus or how to identify their common structural features. See University of Rochester, 358 F.3d at 927, 69 USPQ2d at 1895.
The claims encompass a genus of structurally undefined probiotic products that must treat or prevent obesity, cardiovascular disease, hypertension, type 2 diabetes mellitus, chronic heart failure, ischemic heart disease, ischemia/reperfusion injury, or diabetic nephropathy, as well as decrease the levels of circulating succinate in subjects, or decrease the ratio of succinate producing bacteria to succinate consuming bacteria, in subjects. However, the specification only teaches administering Odoribacter laneus to obese mice where an improvement in glucose tolerance was detected. However, the effect of this bacteria on the circulating succinate levels or the make-up of the gut microbiota is not taught. Additionally, there is no guidance in the specification that this particular bacteria or dosage was able to treat or prevent the broad genus of possible diseases encompassed by the claims. Accordingly, the disclosure of Odoribacter laneus is not representative of the claimed genus of probiotics because the skilled artisan would not be able to distinguish which probiotics and their particular bacterial composition would function as claimed from those that would not.
For claims drawn to a genus, the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species. A “representative number of species” means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. See AbbVie Deutschland GmbH & Co., KG v. Janssen Biotech, Inc., 759 F.3d 1285, 1300, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014) (Claims directed to a functionally defined genus of antibodies were not supported by a disclosure that “only describe[d] one type of structurally similar antibodies” that “are not representative of the full variety or scope of the genus.”). The disclosure of only one species encompassed within a genus adequately describes a claim directed to that genus only if the disclosure “indicates that the patentee has invented species sufficient to constitute the gen[us].” See Enzo Biochem, 323 F.3d at 966, 63 USPQ2d at 1615. Further, University of California v. Eli Lilly and Co., 43 USPQ2d 1398, 1404, 1405 held that:
To fulfill the written description requirement, a patent specification must describe an invention and do so in sufficient detail that one skilled in the art can clearly conclude that “the inventor invented the claimed invention.” Lockwood v. American Airlines, Inc., 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (1997); In re Gosteli, 872 F.2d 1008, 1012, 10 USPQ2d 1614, 1618 (Fed. Cir. 1989) (“ [T]he description must clearly allow persons of ordinary skill in the art to recognize that [the inventor] invented what is claimed.”). Thus, an applicant complies with the written description requirement “by describing the invention, with all its claimed limitations, not that which makes it obvious,” and by using “such descriptive means as words, structures, figures, diagrams, formulas, etc., that set forth the claimed invention.” Lockwood, 107 F.3d at 1572, 41 USPQ2d at 1966.
Thus considering the breadth of the probiotic products required by the claimed methods, their specific required functionalities, and the teachings of the instant specification, it is the conclusion that the specification does not provide an adequate written description of the broadly claimed subject matter.
Enablement
Claims 34, 36-38, and 40-42 are rejected under 35 U.S.C. 112(a) as failing to comply with the enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
There are many factors to be considered when determining whether there is sufficient evidence to support determination that a disclosure does not satisfy the enablement requirements and whether any necessary experimentation is undue. These factors have been described by the court in In re Wands, 8 USPQ2d 1400 (CA FC 1988). Wands states at page 1404,
“Factors to be considered in determining whether a disclosure would require undue experimentation have been summarized by the board in Ex parte Forman. They include (1) the quantity of experimentation necessary, (2) the amount of direction or guidance presented, (3) the presence or absence of working examples, (4) the nature of the invention, (5) the state of the prior art, (6) the relative skill of those in the art, (7) the predictability or unpredictability of the art, and (8) the breadth of the claims.”
The nature of the invention and the breadth of the claims:
The claimed elected invention is broadly directed to methods for treatment of and/or prevention of any disease “associated” with increased levels of circulating succinate in a patient comprising administering any probiotic product (including any Odoribacter spp, Clostridium spp, Phascolarctobacterium spp, Ruminococcus spp, and combinations thereof) to the patient who has had the presence of succinate, in a biofluid sample from the patient, detected above a predetermined threshold level. The claims require that the probiotic product functionally decreases the ratio of succinate producing bacteria to succinate consuming bacteria [claim 38 specifies the ratio as: (Prevotellaceae + Veillonellaceae) / (Odoribacteriaceae + Clostridiaceae); (P+V)/(O+C)] in the intestinal tract of the patient and/or decreases the levels of circulating succinate of the patient, as well as treats or prevents any disease associated with increased levels of circulating succinate. Dependent claims require the patient is obese (claim 36) or has a disease selected from the group consisting of obesity, cardiovascular disease, hypertension, type 2 diabetes mellitus, chronic heart failure, ischemic heart disease, ischemia/reperfusion injury, and diabetic nephropathy (claim 37).
The invention is in a class of inventions which the CAFC has characterized as 'the unpredictable arts such as chemistry and biology" (Mycolgen Plant Sci., Inc. v. Monsanto Co., 243 F.3d 1316, 1330 (Federal Circuit 2001)).
The amount of direction or guidance/Presence and absence of working examples:
With regard to circulating succinate levels, obesity, and gut microbiota, the specification teaches:
in a cohort of 91 patients stratified according to obesity and T2DM, plasma succinate levels were significantly higher in obese than lean individuals. The specification teaches that a multiple regression model adjusted for age and gender showed that BMI and glucose were the main determinants of circulating succinate levels (page 54, lines 10-20).
The specification teaches that 16S rRNA gene sequencing revealed that in a second independent cohort of twenty subjects, Firmicutes/Bacteroidetes ratio in obese subjects was increased, while there was a decrease in richness and biodiversity at the phylum and genus level (figures 5B-C, page 55, lines 20-32). The specification teaches there was an increase in some succinate producing (Prevotellaceae and Veillonellaceae) bacteria and a decrease in some succinate consuming (Odoribacteraceae and Clostridaceae) bacteria in obese vs non obese individuals (page 56).
The specification teaches whole genome shotgun sequencing in a third cohort of 17 subjects revealed an increase in Veillonellaceae correlated with circulating succinate levels in obese vs lean individuals (page 57).
The specification teaches a fourth cohort of 9 obese subjects were assessed for succinate levels following a dietary weight loss intervention (page 58). The specification teaches that serum succinate levels decreased as did succinate producing bacteria Prevotellaceae and Veillonellaceae. The specification teaches a correlation between circulating succinate levels and (P+V)/(O+C).
The specification teaches that a cohort of 19 subjects were counseled on healthy habits and studied at baseline and 2 years thereafter. The specification teaches no significant differences in body weight were observed. The specification teaches that at the end of the 2 year follow-up, an increase in the (P+V)/(O+C) ratio was associated with increased in succinate levels in some subjects while a decrease in the ratio was associated with a decrease in succinate levels. However, since no significant body weight differences were found in the patients, the effect of this ratio and the effect of succinate levels on the health of this patient population is unclear.
With regard to the actual administration of a probiotic, the specification teaches that C57/B16 obese mice were treated with Odoribacter laneus with 100 uL bacteria at 1/109CFU/mL. The specification teaches that glucose tolerance increased in the Odoribacter laneus treated animals. However the specification does not teach whether circulating succinate levels were decreased, or whether the ratio of succinate producing bacteria to succinate consuming bacteria was decreased in Odoribacter laneus treated animals. The specification does not teach the composition of any probiotic products that decrease the levels of circulating succinate in subjects, or which decrease the ratio of succinate producing bacteria to succinate consuming bacteria, in subjects. The specification does not teach the composition of any probiotic that can treat or prevent obesity, cardiovascular disease, hypertension, type 2 diabetes mellitus, chronic heart failure, ischemic heart disease, ischemia/reperfusion injury, or diabetic nephropathy.
The state of the prior art and the predictability or unpredictability of the art:
While there are a variety of studies that examined the effects of microbial imbalance in the gut as well the manufacture of probiotics, the unpredictability of treating or preventing particular diseases, including hypertension, CVD, T2DM, etc, using probiotics is acknowledged by the prior and post filing date art.
Thushara (Thushara et al; Food Func. 2016, vol 7, p 632-642) teaches that some findings suggest that microbial imbalance of the gut may play a role in the pathogenesis of cardiovascular disease (CVD), resulting in studies that delved into the aspect of altering gut microbiota with probiotics to treat or prevent CVD (see abstract, whole document). However, Thushara teaches that ambiguity exists regarding the exact strains and dosages of the probiotics that will bring about positive health effects and that additional factors such as immunity and genetics of individuals may influence the efficacy of probiotics. With regard to T2DM, Thushara teaches the results of several studies on the effects of probiotic supplements including studies that showed positive effects on fasting glucose and glucose intolerance while others did not see a significant effect on FPG, insulin, CRP, or lipid profile (see page 640, col 1). Thushara teaches that the assessment of probiotic efficacy on large human populations is extremely diverse due to many confounding factors such as diet, endotoxin content of ingested food, frequency of food intake, physical activity, glucose metabolism, insulin and other gut hormones.
The post filing date reference of Khan (Khan et al; Molecular Nutrition Food Research, vol 68, pages 1-14; 2024) also provides a review of the effects of probiotics on treatment of CVD, and corroborates the unpredictability taught by Thushara. Khan also teaches that ambiguity exists regarding strain dosages, and interactions with confounding factors. Khan teaches that the relationship between gut microbiota and CVD is a promising area of investigation but that the current knowledge regarding the efficacy of different probiotic formulations and their appropriate doses need further investigation, including clinical trials, to provide more concrete evidence regarding the usage of probiotics in treating CVD.
Further, the post filing date art of Lopez-Yerena (Lopez Yerena et al; Nutrients, vol 17, pages 1-22, 2025) also teaches that treatment of CVD with probiotics requires further research because of the many factors that influence the effect of probiotics (see abstract). Lopez-Yerena teaches that oral probiotics face several challenges on their journey through the gastrointestinal tract, including the adverse gastrointestinal environment characterized by low pH in the stomach and bile salts in the small intestine (see page 2). Lopez-Yerena teaches that probiotic design is an important consideration that can affect the functionality of a probiotic, including the dosages which are regulated by different agencies. (see page 3). Lopez-Yerena additionally reviews different studies that assessed the effects of probiotics on different health conditions, including, for example, hypertension. Lopez-Yerena teaches that out of 5 interventional studies, the beneficial effect of probiotics on SBP and DBP was only evidenced in two studies (page 5). With regard to T2DM, Lopez-Yerena teaches that there was no consensus among studies which studied the effects of multi-strain probiotics on the level of HbA1c, for example, in T2DM patients with one study showing an increase, three showing a decrease, and three showing no change (page 8). Additional contradictory findings are summarized at page 11, including the effect of probiotics on blood pressure, glucose and insulin. Lopez-Yerena teaches that as of 2025, further research is warranted to elucidate the mechanisms by which probiotics exert beneficial effects, including determining the optimal probiotic strains, appropriate dosage, treatment duration, and optimal delivery vehicle.
The level of skill in the art:
The level of skill in the art is deemed to be high.
The quantity of experimentation necessary:
To practice the invention as broadly as it is claimed, the skilled artisan would be required to undertake an enormous amount of trial and error experimentation to treat or prevent the large group of diseases encompassed by the claims using probiotic products, including with bacteria as set forth in the dependent claims. While the specification teaches associations between circulating succinate levels and obesity, it does not demonstrate a causal effect, nor does it teach the strains, dosages, mode of delivery, or treatment duration for treatment or prevention of the diseases encompassed by the claims, using probiotics. The single experiment using obese mice treated with Odoribacter laneus does not provide the necessary guidance needed by the skilled artisan to be able to make or use the invention as broadly claimed. This is evidenced by the prior and post filing date art. Practice of the invention as broadly claimed requires a large amount of trial and error experimentation, requiring a large amount of inventive effort, with each of the many intervening steps providing no indication of success.
Thus given the broad claims in an art whose nature is identified as unpredictable, the unpredictability of that art, the large quantity of research required to define these unpredictable variables, the lack of guidance provided in the specification, balanced only against the high skill level in the art, it is the position of the examiner that it would require undue experimentation for one of skill in the art to perform the method of the claim as broadly written.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to examiner Jehanne Sitton whose telephone number is (571) 272-0752. The examiner is a hoteling examiner and can normally be reached Mondays-Fridays from 8:00 AM to 2:00 PM Eastern Time Zone.
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/JEHANNE S SITTON/Primary Examiner, Art Unit 1682