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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 21 July 2025 has been entered.
DETAILED ACTION
Applicant’s amendment filed on 21 July 2025 is entered. Claim 1 is amended and claim 6 is cancelled. Claims 1, 3-5, and 7-22 are pending. Claims 8-22 remain withdrawn. Claims 1, 3-5, and 7 are under examination.
Claim Objections
Claim 1 is objected to because of the following informalities: in step (c), the adverb “non-invasively” should precede the verbs “observing and measuring”.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1, 3-5, and 7 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Regarding claim 1, it is unclear what the metes and bounds of the claim term “non-invasively” are. The specification lacks a special definition for the term, and the disclosure does not describe any specific method steps or parameters that allow one of ordinary skill in the art to readily determine whether any observation or measurement is non-invasive as opposed to invasive. Thus, one of ordinary skill in the art would not be able to readily determine the scope of observations and measurements that are encompassed by the claim term “non-invasively”.
Claims 3-5 and 7 are dependent on claim 1 and so are indefinite for the same reasons.
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.
Claims 1 and 4 are rejected under 35 U.S.C. 103 as being unpatentable over Keller et al. (Spores of Bacillus coagulans GBI-30, 6086 show high germination, survival and enzyme activity in a dynamic, computer-controlled in vitro model of the gastrointestinal tract, Beneficial Microbes, 2019; 10(1): 77-87) in view of Ding et al. (Novel scheme for non-invasive gut bioinformation acquisition with a magnetically controlled sampling capsule endoscope, Gut 2021;70:2297–2306, published 15 January 2021).
Regarding claim 1, Keller teaches a method of determining the effective germination of spores of orally administered probiotic Bacillus species in an in vitro human gastrointestinal model (Keller Abstract). A Bacillus containing probiotic composition was provided and orally administered in the gastrointestinal model, and samples of ileal efflux were collected and a subsample was plated every hour for 6h for viable counts, including spores and germinated cells, in order to observe and measure the effective germination of the administered Bacillus probiotic over time (Keller Abstract). Keller observed that survival of the administered probiotic Bacillus in the form of spores and germinated cells in the ileal efflux was on average 51%, and of those that survived, 93% germinated (Keller Abstract). Therefore, Keller teaches a method of demonstrating effective germination of simulated orally administered probiotic Bacillus species in a simulated ileum of an in vitro human gastrointestinal model, which correlates very closely to in vivo human GI tract conditions (Keller Conclusions sent. 1).
Keller teaches that the effective germination of the Bacillus spores from the ileum was observed over the course of 6 hours (Keller Abstract), not 24 hours as claimed. However, one of ordinary skill in the art would have found it prima facie obvious to simply continue repeating the same method step of plating the ileal efflux to determine viable counts beyond the 6 hours Keller did. One of ordinary skill in the art would have been motivated to do so in order to monitor the length of time required for the administered composition of Bacillus spores to travel in its entirety down the small intestine of a human, and furthermore to determine if colonization of the small intestine was observed (e.g. Bacillus cells/spores would continue to be detected or would increase over time). One of ordinary skill in the art would have a reasonable expectation of success because the observation and measurement step of Keller’s method would not need to be fundamentally changed, but rather merely continued over a longer period of time, and thus the repetition of the step would be expected to be successful.
Keller does not teach a non-invasive means of observing and measuring the Bacillus germination.
Ding teaches a non-invasive, precise, and accurate method for sampling ileal GI content in vivo using a magnetically controlled sampling capsule endoscope (MSCE), and observing and measuring the intestinal microbiota in those ileal samples after sampling (Ding Abstract). Ding teaches that previous approaches to obtain intestinal samples required invasive, inconvenient, and laborious procedures such as endoscopy (Ding. pg. 2298 para. 3), but in contrast their MSCE-mediated sampling procedure enabled non-invasive, contactless, and accurate intestinal content sampling in order to acquire intestinal bioinformation such as microbiota composition (Ding pg. 2298 para. 4).
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the present invention to modify Keller’s method of demonstrating effective germination of Bacillus spp. spores by performing Keller’s method in an in vivo real gastrointestinal tract as opposed to the in vitro modeled gastrointestinal tract taught by Keller, and to use Ding’s non-invasive MSCE-mediated sampling procedure to collect the subject’s ileal samples that Keller’s method requires to be regularly plated in order to observe and measure the effective germination of the probiotic Bacillus spp. spores.
One of ordinary skill in the art would have been motivated to apply Keller’s method in an in vivo gastrointestinal environment in order to observe the germination effectiveness of orally administered probiotic Bacillus spores in a real in vivo gastrointestinal tract, with the additional objective of determining the mechanism of action of orally administered probiotic Bacillus on real GI tracts and cholesterol, which is suggested by Keller (Pg. 82-83 bridging para.). One of ordinary skill in the art would have had a reasonable expectation of success in applying Keller’s method in an in vivo gastrointestinal environment because Keller’s method of demonstrating effective germination of administered Bacillus spp. spores uses a validated, dynamic in vitro model of the human gastrointestinal tract, including a model of the human ileum (TIM-1). TIM-1 is a validated model which closely and dynamically simulates a real human GI tract by modulating numerous environmental conditions, including gastric acidity and bile concentrations which greatly influence probiotic survival (Keller p. 78 para. 4). The TIM-1 model also modulates the concentrations of electrolytes, enzymes, bile, and pancreatic juice, and simulates the processes of gastric emptying, absorption of nutrients in the body, intestinal residence time, and intestinal pH-curves, all of which mimic the situation as found in humans for semi-solid foods (Keller sec. 2 para. 1). Furthermore, the method of Keller comprises the step of administering the probiotic Bacillus spores together with actual breakfast food (comprising bread, milk, margarine, jam, ham, cheese, cornflakes, and orange juice) in the form of a complete meal to the gastric compartment of the model (simulation of the stomach) (Keller p. 79 para. 3). Keller further teaches that administration of the composition to the gastric compartment of the model is considered “orally” administered (Keller abstract and sec. 3 para. 1). When the complete teachings of Keller are considered, one of ordinary skill in the art would have concluded that the in vitro model of Keller very closely simulates the human GI tract and the oral administration of a food-Bacillus probiotic composition to said GI tract, such that the model is so sufficiently similar to the human GI tract that the method of Keller’s in vitro experiment would be reasonably expected to successfully determine the effective germination of orally administered probiotic Bacillus spores in a human ileum in vivo.
One of ordinary skill in the art would have been motivated to use Ding’s non-invasive MSCE-mediated sampling procedure to collect the subject’s ileal samples that Keller’s method requires to be regularly plated in order to measure the effective germination of the administered probiotic Bacillus spp. spores because other approaches to obtain intestinal samples require invasive, inconvenient, and laborious procedures such as endoscopy (Ding. pg. 2298 para. 3), but in contrast Ding’s MSCE-mediated sampling procedure enables non-invasive, contactless, and accurate intestinal content sampling (Ding pg. 2298 para. 4). One of ordinary skill in the art would have had a reasonable expectation of success because Ding taught that their MSCE-mediated ileal sampling procedure collected samples that are comparable to the established invasive surgical procedures (Ding figs. 2-3); thus one of ordinary skill in the art would have recognized that Ding’s non-invasive sampling procedure predictably collects ileal samples that are comparable to those collected by traditional surgery, but do not require the invasive, inconvenient, and laborious procedures those traditional surgeries require.
Regarding claim 4, Keller teaches that the administered probiotic Bacillus composition comprised 109 CFU (1 billion CFU) (Keller p. 79 para. 3).
Claims 3, 5, and 7 are rejected under 35 U.S.C. 103 as being unpatentable over Keller and Ding as applied to the 103 rejection of claims 1 and 4 above, and further in view of Deaton et al. (US 11,160,838 B2 published 2 November 2021, effectively filed 9 August 2019).
Keller and Ding do not teach that the ingested probiotic Bacillus comprises Bacillus subtilis subspecies inaquosorum having accession number NRRL B-67989, that the administered Bacillus probiotic composition comprises 0.1-10% by weight Bacillus spores and 90-99.9% by weight one or more carriers, or that the composition is in the form of a capsule or tablet.
Regarding claim 3, Deaton teaches a probiotic composition comprising Bacillus subtilis subspecies inaquosorum strain DE111® having an accession number of NRRL B-67989 (Deaton column 24 lines 6-17 and column 31 lines 26-28).
Regarding claim 5, Deaton teaches the probiotic in the composition can be from 0.5% to 10% by weight (Deaton column 28 lines 20-34), which overlaps with the claimed range. Deaton also teaches that the composition can further comprise carriers (Deaton column 32 lines 12-14). However, Deaton fails to specifically teach the weight percentage of those carrier compounds in the total composition. One of ordinary skill in the art would have found it obvious that in a composition that combines a probiotic microorganism and carriers, and the probiotic microorganism is taught to be 0.5 to 10% by weight of the total composition, the carriers would comprise the other 90-99.5% by weight of the total composition.
Regarding claim 7, Deaton teaches that the composition can be in the form of capsules or tablets (Deaton column 32 lines 14-15).
Therefore, it would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the present invention to modify Keller’s method of demonstrating effective germination of probiotic Bacillus species to use Deaton’s compositions comprising Bacillus subtilis subspecies inaquosorum strain DE111® having an accession number of NRRL B-67989. One of ordinary skill in the art would have been motivated to do so because 1) Deaton’s Bacillus subtilis subspecies inaquosorum strain having an accession number of NRRL B-67989 (DE111®) is taught to be able to produce spores that protect the cells from harsh conditions (such as gastric conditions) until proper germination conditions were present, and that the DE111® strain would confer the same and/or analogous probiotic health benefits on the human GI tract as the Bacillus coagulans GBI-30 6086 (BC30) strain taught by Keller (Deaton col. 4 lns. 23-39, col. 25 lns.11-20, and col.19 lns.49-52; Keller intro. para. 1), and thus the DE111® strain of Deaton would be expected to have comparable probiotic characteristics as the BC30 strain of Keller; and 2) in order to determine the effective germination properties of an administered probiotic composition comprising the specific strain of Bacillus subtilis subspecies inaquosorum strain having an accession number of NRRL B-67989 in a human. One of ordinary skill in the art would have had a reasonable expectation of success in this endeavor because Keller teaches the method was able to determine the effective germination of an administered probiotic Bacillus species in an in vitro human small intestine model (TIM-1), and therefore one of ordinary skill in the art would have reasonably expected that by using the method of Keller they would be able to determine the effective germination of the specific Bacillus strain Bacillus subtilis subspecies inaquosorum having an accession number of NRRL B-67989.
Response to Arguments
Applicant's arguments filed 21 July 2025 have been fully considered but they are not persuasive.
Regarding Applicant’s arguments that it would not have been obvious to apply Keller’s method in vivo because motivation and predictability in the chemical arts are particularly difficult because of the difference between in vitro data and in vivo behavior in the human digestive system such as bioavailability and nutrient absorption, thus it would have required undue experimentation to obtain the claimed results in a living human using Keller as a guide (Remarks pg. 5 last para. through pg. 6 para. 2):
A general statement that motivations and predictability in the chemical arts is particularly difficult is insufficient to overcome the prima facie case of obviousness at least because no evidence has been made of record which clearly demonstrates these difficulties as they apply to the instant case.
Keller’s method of demonstrating effective germination of administered Bacillus spp. spores uses a well-known, validated, and dynamic in vitro model of the human gastrointestinal tract, including a model of the human ileum (TIM-1). TIM-1 is a validated model which closely and dynamically simulates a real human GI tract by modulating numerous environmental conditions, including gastric acidity and bile concentrations which greatly influence probiotic survival (Keller p. 78 para. 4). The TIM-1 model also modulates the concentrations of electrolytes, enzymes, bile, and pancreatic juice, and simulates the processes of gastric emptying, absorption of nutrients in the body, intestinal residence time, and intestinal pH-curves, all of which mimic the situation as found in humans for semi-solid foods (Keller sec. 2 para. 1). Although Keller’s disclosure does not specifically take into account some bioavailability factors as laid out by Applicant on pg. 6 para. 1 of the Remarks, these "host factors" dictating nutrient absorption are not what is being measured by Keller’s method, nor the instant method. Keller’s method simply determines the effective germination of orally administered probiotic Bacillus spp. compositions by taking samples from the ileum and plating them, both of which are actions that overlap with the instant limitation "observing and measuring…the effective germination". When the complete teachings of Keller are considered, one of ordinary skill in the art would have concluded that the in vitro model of Keller very closely simulates the human GI tract and the oral administration of a food-Bacillus probiotic composition to said GI tract, such that the model is so sufficiently similar to the human GI tract that the method of Keller’s in vitro experiment would be reasonably expected to successfully determine the effective germination of orally administered probiotic Bacillus spores in a human ileum in vivo.
Regarding Applicant’s arguments that since Keller discloses an in vitro method, the concept of invasiveness is not pertinent or suggested, so the noninvasive features of the present claims are distinct from Keller (Remarks pg. 6 para. 3), the 103 rejection is based on Keller in view of Ding, not Keller alone. As discussed above, one of ordinary skill in the art would have found it reasonably predictable that performing Keller’s method in a human gastrointestinal tract in vivo would allow one of ordinary skill in the art to successfully determine the effective germination of Bacillus spp. spores in the ileum of a human that was orally administered the probiotic Bacillus spp. composition. However, in order to perform Keller’s method in vivo, one of ordinary skill in the art must collect an ileal sample from the human’s gastrointestinal tract. Ding teaches one such ileal sampling procedure which non-invasively collects in vivo ileal samples that are comparable to samples obtained by traditional surgical procedures, but does not require the invasiveness, inconvenience, and labor required by those surgical procedures. Thus, one of ordinary skill in the art would have recognized that there is an advantage to use Ding’s non-invasive sampling procedure to collect the in vivo ileal samples used in Keller’s method.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Alexander M Duryee whose telephone number is (571)272-9377. The examiner can normally be reached Monday - Friday 9:00 am - 5:00 pm.
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/Alexander M Duryee/Examiner, Art Unit 1657
/LOUISE W HUMPHREY/Supervisory Patent Examiner, Art Unit 1657