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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 16 Jan 2026 has been entered. The request for continued examination was filed 24 Nov 2025, but the entered submission was applicant’s additional submission filed 16 Jan 2026 in response to the non-responsive amendment notice.
Claim Status
The amended claim set filed 16 Jan 2026 is acknowledged. Claims 1-7 and 9-14 are currently pending. Of those, claims 1-6 and 9 are currently amended, claims 10-14 are new and no claims are withdrawn. Claim 8 is cancelled. Claims 1-7 and 9-14 will be examined on the merits herein.
Response to Arguments
The Applicants’ arguments filed 16 Jan 2026 are acknowledged. For clarity, in this action, said arguments will be referred to as “Remarks” and the Final Office Action mailed 23 July 2025 will be referred to as “NFOA.”
In this action, references to the specification will use paragraph numbers from the Pre-Grant Publication US-20230042485-A1 in order to avoid confusion due to different page and line numbers across different versions of the specification.
Objection(s) and Rejection(s) Withdrawn
The objection to the specification related to the sequence disclosure (FOA par. 10) is withdrawn in view of the amendment.
The rejections of claims 1-8 under 35 U.S.C. 112(b) related to claims 1 (FOA par. 12-13) and claims 2-3 (FOA par. 14-15) are withdrawn in view of the claim amendments and arguments. The rejections under 35 U.S.C. 112(b) of claim 4 (FOA par. 45), and claim 9 (FOA par. 46-48) are withdrawn in view of the claim amendments and arguments.
The rejection under 35 U.S.C. 112(b) related to claim 1 (FOA par. 44) is withdrawn in view of the substantial claim amendments, but see the highly similar new rejection below.
The rejection under 35 U.S.C. 112(a) related to claim 1 (FOA par. 50-51) is withdraw in view of the claim amendments.
Rejection(s) Maintained
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claim Rejections - 35 USC § 112(a)
Claims 1-7 and 9 remain rejected and claims 10-14 are newly rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The prior rejection has been updated to reflect the claim amendments; a response to applicant’s argument follows the rejection.
The factors to be considered in determining whether a disclosure would require undue experimentation include: (A) The breadth of the claims; (B) The nature of the invention; (C) The state of the prior art; (D) The level of one of ordinary skill; (E) The level of predictability in the art; (F) The amount of direction provided by the inventor; (G) The existence of working examples; and (H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure. In re Wands, 8 USPQ2d, 1400 (CAFC 1988) and MPEP 2164.01. Although all factors were considered, the Wands factors that were most relevant for this decision are discussed in detail below.
The breadth of the claims: The claims require a method to identify a consortium of probiotic strains for promoting a degradation of gluten and gluten-derived peptides, comprising performing sequential experiments to identify the most suitable strains. The claim does not require any properties of the initial bacteria, and does not require that one begin with bacteria that are already known to have the properties being selected for in the experimental method. The only limitation is that the final pool of bacteria, and therefore also the initial pool of bacteria be from “the group consisting of Lactobacillus, Bacillus, Pediococcus and Weissella”. In particular, the claims require:
“(a) identifying two or more probiotic bacterial strains that undergo less than a 2 log loss of colony forming units (CFUs) after exposure to a gastric pH of 1 to 4 for at least 30 minutes and after exposure to an intestinal pH of 5.5 to 8.5 for at least 30 minutes” The broadest reasonable interpretation of “exposure” in the first step uses as few as two strains.
“(b) assaying proteinase activities of the two or more probiotic bacterial strains of (a) and identifying at least two strains that decrease an initial gluten level of at least 5,000 ppm by 10 to 70%”
“(c) assaying the proteinase activities of the two or more probiotic bacterial strains of (b) to identify at least two probiotic bacterial strains that have an aminopeptidase N (PepN), PepI, PepO, prolyl endopeptidyl peptidease (PEP), PepX and/or PepQ peptidase activity of at least 1 U per gram of cells or cytoplasm of the two probiotic bacterial strains on a suitable peptide substrate” Note that the assayed proteinases are different proteins than the peptidases PepN, PepI, etc. that are used to define the identified bacterial strains. The instant specification uses the terms “peptidase” and “proteinase” in non-overlapping manners (“peptidase and proteinase activities” [0074]). The specification refers to measuring “Proteinase Activities of Strains Towards Gluten” in step 3 and specifically measuring “Proteinase (cell-envelope-associated proteinase) activity” [0058, emphasis added]. In contrast, the specification refers to “Peptidase Activities of Strains Towards Synthetic Substrates” in step 4 “to assay the cytoplasm peptidase activities,” [0061, emphasis added] which include “General aminopeptidase type N (PepN), proline iminopeptidase (PepI), X-prolyl dipeptidyl aminopeptidase (PepX) activities of the cytoplasmic extracts” [0062].
“(d) combining the at least two probiotic strains from (c) to produce a consortium of probiotic strains that in aggregate have at least 1 U peptidase activity per gram of cells or cytoplasm for each of peptidases PepN, PepI, PepO, PepX, and PepQ; and”
“(e) selecting a consortium of (d) that reduces an initial gluten level of at least 5,000 ppm to a concentration of less than 200 ppm of hydrolyzed and residual gluten and that degrades the peptides of SEQ ID NOs: 1, 2, 3, and 4 by more than 50%.”
Claim 2 has additional steps: “determining hydrolysis of gluten during wheat bread digestion by the consortium of strains under simulated gastrointestinal conditions and selecting a consortium with a degradation capacity of the gluten content in wheat bread during 6 - 24 hours to less than 20 ppm and absence of gluten-derived epitopes of SEQ ID NOS: 1. 2. 3 and 4 after 180 min of simulated intestinal digestion; and
determining immunogenicity of the consortium of strains by using small intestinal tissue explants from celiac disease (CD) patients by determining the expression of the cytokines Interleukin 2 (I7L-2), interleukin 10 (IL- 10), and interferon gamma (IFN-y) after an incubation of 6-48 h under gastro- intestinal conditions and selecting a consortium of with an immunogenicity of not more than the negative control.”
The “selecting” and “identifying” limitations in steps (a, b, c, e) of claim 1 and the two steps of claim 2 are interpreted as being required. In other words, to successfully use the method as claimed, there must be strains or consortia to select at each step; if all strains or consortia fail to meet the benchmark, then the method has not been successful.
New claim 9 recites a process of producing a consortium of bacteria (not limited to the species in claim 1) that reduces an initial gluten level of at least 5,000 ppm to a concentration of hydrolyzed and residual gluten of less than 200 ppm comprising:
(1) “contacting probiotic strains with simulated gastric conditions at pH 1-4 for at least 30 mins and contacting said probiotic strains with simulated intestinal conditions at pH 5.5-8.5 for at least 30 mins and selecting those probiotic strains that undergo less than a 2 log loss of colony forming units (CFUs)” This is similar to claim 1 step (a). The broadest reasonable interpretation of “probiotic strains” in the first step is as few as two strains.
(2) “contacting the strains undergoing less than a 2 log loss of CFUs with gluten and selecting those strains that decrease an initial gluten level of at least 5,000 ppm by 10 to 70%” This is similar to claim 1 step (b).
(3) “determining the peptidase activity of the strains that decrease an initial gluten level of at least 5,000 ppm by 10 to 70% and selecting the strains that exhibit at least 1 U activity per gram of bacteria for at least one peptide selected from the group consisting of aminopeptidase type N (PepN); PepI, PepO, Prolyl endopeptidyl peptidase (PEP); PepX, and PepQ peptide hydrolase” This is similar to claim 1 step (c), but differs in measuring peptidase activity instead of proteinase activity.
(4) “combining at least two of said strains with other probiotic strains having at least 1 U peptidase activity per gram of bacteria for each of PepN, PepI, PepO, PepX and PepQ to form a first consortium” This is similar to claim 1 step (5) in that the resulting consortium has 1 U peptidase activity for each of PepN, PepI, PepO, PepX and PepQ, but differs in that the strains are combined with some other, not previously defined consortium, rather than the strains being combined together to produce a consortium. Also the activity is only defined per gram of bacteria rather than per gram of cells or cytoplasm as in claim 1.
(5) “determining the peptidase activity of the resulting consortium towards the 12-mer peptide QLQPFPQPQLPY (SEQ ID NO: 1 ), the 14-mer peptide PQPQLPYPQPQSFP (SEQ ID NO: 2), the 20-mer peptide QQLPQPQQPQQSFPQQQRPF (SEQ ID NO: 3 ), and the 33- mer peptide LQLQPFPQPQLPYPQPQLPYPQPQLPYPQPQPF (SEQ ID NO: 4)” This step is not recited in claim 1.
(6) “selecting a second consortium with a peptidase activity that degrades all four epitopes by more than 50% and that reduces the initial gluten level of at least 5000 ppm to a concentration of hydrolyzed and residual gluten of less than 200 ppm, wherein said reduction of initial gluten level occurs under simulated gastric conditions of pH 1-4 for at least 30 minutes and intestinal conditions of pH 5.5-8.5 for at least 30 minutes” This are the same consortium properties as claim 1 step (e), but also defines the conditions where gluten level are measured.
For claim 1 step (a) and claim 9 steps (1) and (6), the broadest reasonable interpretation of “gastric conditions at pH 1-4” and “intestinal conditions at pH 5.5 - 8.5” is that nothing is required other than the listed pH, due to the lack of definition for “gastric conditions” and “intestinal conditions” in the specification and the art. So for example, water (pH 7) meets the broadest reasonable interpretation of “intestinal conditions at pH 5.5 - 8.5.” For the claim 2 step of “simulated intestinal digestion”, this is interpreted as having antecedent basis in “intestinal conditions at pH 5.5 - 8.5” from claim 1 (a), and water would also meet this condition.
The existence of working examples: In Example 1 (pg. 14), the specification begins with a library of < 400 bacteria and tests resistance to simulated gastric and intestinal conditions and selects strains showing a decrease less than 2 log of the initial CFU (claim 1 step (a) and claim 9 step (1)). Only 119 strains were selected.
In Example 2 (pg. 14-15), the specification tests the activities of peptidase enzymes PepN, PepI, PepX, PepO, PepP (referred to as PEP in the claims) for “all 119 strains… showing resistance to simulated gastrointestinal conditions” (pg. 14 ln. 20-21) (assay step not recited in claim 1, claim 9 step (3)). Figure 2 teaches that 24 strains show “very high peptidase activities (at least for one peptidase activity)” (pg. 15 ln. 1-2). Example 2 is not the same as claim 1 step (c) or claim 9 step (3) because it does not measure levels of PepQ and the specification does not teach that this “very high” level of peptidase activity meets the selection criteria of “at least 1 U per gram of” cells/bacteria or cytoplasm as required by claim 1 steps (c) and (d) and claim 9 steps (3) and (4).
Example 3 (pg. 15-16) shows peptidase activities of six probiotic consortia against the 12-mer, 14-mer, 20-mer and 33-mer (SEQ ID NOs: 1-4, Figure 3), assay step not recited in claim 1 but required by (e), assay performed in claim 9 step (5) and required by step (6). All consortia at least partially hydrolyze the peptides (Figure 3), but the specification does not teach that the “Partially Hydrolyzed” results meet the steps (e) and (6) limitation of “degrades all four epitopes by more than 50%”.
Example 4 (pg. 16-19 and 22) teaches performing a gluten hydrolysis experiment using simulated gastric and intestinal conditions (similar to claim 1 steps (b) and (e) and claim 9 steps (2) and (6) and claim 2) on 16 consortia comprising 22 strains. The initial gluten concentration was 7,000 ppm, so a decrease by 10-70% as in claim 1 step (b) and claim 9 step (2) corresponds to a final gluten concentration of 2,100-6,300 ppm. None of the consortia have residual gluten content within this range at any timepoint (Table 2, pg. 20-21). Related to claim 2, only 2 of the consortia have residual gluten content of less than 20 ppm at 6 hours and 10 consortia have residual gluten content of less than 20 ppm at 24 hours (Table 2, pg. 20-21). Also, the example teaches that simulated intestinal fluid was added after 180 min of gastric digestion (pg. 18 ln. 27-28), so “after 180 min of simulated intestinal digestion” (recited in claim 2) corresponds to the 6 hour (360 min) timepoint. No consortia had an absence of gluten peptides (including but not limited to the 12-mer, 14-mer, 20-mer, and 33-mer) at the 6 hour timepoint (Table 2, pg. 20-21).
Example 5 (pg. 22-25) teaches measuring immunogenicity of dough digested by the consortia (pg. 23 ln. 12-24) (recited in claim 2) and measured IL-2, IL-10, and IFN-γ cytokines released by biopsy tissue from Celiac disease patients (Figure 5). Under these conditions the immunogenicity of the consortium (see claim 2) cannot be differentiated from immunogenicity of the gluten present in the dough.
Thus, the specification does not provide any working examples of the method as claimed. In addition to what was pointed out above, the examples also do not teach claim 9 step (4) because they do not teach combining at least 2 of the strains with some other consortium that in aggregate has at least 1 U/g peptidase activity for peptidases PepN, PepI, PepO, PepX and PepQ.
A working example is not required to have support for the claimed method; however, these differences are relevant for whether the specification as a whole provides evidence to support enablement of a claimed method that was not performed.
The amount of direction provided by the inventor: The specification teaches that “several microbiota-targeted approaches have been developed in search for treatment options for gluten-related disorders.” (pg. 3 ln. 30-31), but “So far, all these attempts have failed to deliver a consistent benefit to people in need thereof. Moreover, the application of peptide hydrolases has been discussed as a possible health risk, as they may cause incomplete digestion of gluten, triggering the release of toxic epitopes, which would exacerbate and not ameliorate gluten toxicity [11]. Efficacy of enzyme treatments for CD patients is also limited by poor proteolytic resistance, and limited extent and duration of enzymatic activity during gastrointestinal transit [12].” (pg. 3 ln. 34- pg. 4 ln. 4). “We believe that the lack of benefit from probiotic interventions results from improper selection and blending of probiotic strains. ... Such process has so far not been described and is the subject of this invention.” (pg. 4 ln. 21-24). The specification teaches other art in the field (pg. 4-5). In particular, applicant states that several studies teach that probiotic bacteria may have weak or no proteolytic activity against the 33-mer and other peptides (pg. 5 ln. 17-23), which is consistent with the experimental evidence in the Examples.
The amount of direction provided by the inventor about the level of predictability: Claim steps that only require performing assays have a high level of predictability because the assay steps are known.
Claim 1 step (a) and claim 9 step (1) the level of predictability is low. Example 1 only identified 119 strains out of <400 tested (approximately a quarter of strains tested could have been identified).
Claim 1 step (b) and claim 9 step (2) the level of predictability is very low. Example 4 teaches that none of the 16 consortia comprising 22 strains successfully can be identified as decreasing the initial gluten level of at least 5,000 ppm by 10 to 70%.
Claim 1 step (c) and claim 9 step (3) the part of the method of identifying/selecting at least two strains with peptidase levels of at least 1 U per gram of cells or cytoplasm has very low predictability. Example 2 does not use the claimed threshold for peptidase levels, so the specification does not teach that any strains meet the claimed threshold. Also, Example 2 teaches that only 24 out of 119 strains tested show very high peptidase activities for at least one peptidase (approximately a quarter of strains tested could have been identified by the example’s threshold). Also, levels of PepQ have not been measured.
Claim 1 step (d) the level of predictability is moderate because combining the strains is itself predictable, but relies on having bacterial strains that successfully passed the three prior steps which each have low predictability. For claim 9 step (4) the level of predictability is low based on the specification, including its teachings about the art at the time of filing, because the strains are combined with “other probiotic strains” that have the claimed peptidase activities, but the specification does not teach how to obtain these “other probiotic strains” and instead teaches that existing probiotic-based approaches have been unsuccessful.
Claim 1 step (e) and claim 9 step (6) the level of predictability is for the selected strain having the function of “reduces an initial gluten level of at least 5,000 ppm to a concentration of less than 200 ppm of hydrolyzed and residual gluten” is moderate to low, because step (b) or (2) selects for strains that leave a much higher level of residual gluten (a decrease by 10-70% corresponds to a final gluten concentration of 2,100-6,300 ppm) the specification has not shown that the combination into a consortium would reduce the residual gluten level below the claimed threshold. Also, Example 4 shows that the success of consortia at reaching this benchmark is only 2-10 consortia out of 16 tested, depending on the timepoint being considered.
Claim 1 step (e) and claim 9 step (6) the level of predictability is for the selected strain having the function of “that degrades the peptides of SEQ ID NOS: 1, 2, 3 and 4 by more than 50%” is difficult to determine but appears to be low. Example 3 does not report peptide degradation in percentage values and Example 4 only reports levels for all gluten fragments (not the claimed peptides) and does not give a clear way to calculate degradation because more peptides are produced from gluten throughout the test period in addition to being degraded. Applicant’s teaching that several studies teach that probiotic bacteria may have weak or no proteolytic activity against the 33-mer and other peptides (pg. 5 ln. 17-23) suggests the predictability is low.
Claim 2 the level of predictability for the step of selecting a consortium with a degradation capacity of the gluten content in wheat bread during 6 - 24 hours to less than 20 ppm is low because Example 4 shows that the success of consortia at reaching this benchmark is only 2 consortia out of 16 tested reached this threshold by 6 hours.
Claim 2 the level of predictability for the step of selecting a consortium with absence of gluten-derived epitopes of SEQ ID NOS: 1. 2. 3 and 4 after 180 min of simulated intestinal digestion is very low because Example 4 shows that none of the consortia had an absence of gluten peptides (including but not limited to the 12-mer, 14-mer, 20-mer, and 33-mer) at the 6 hour timepoint.
Claim 2 the level of predictability for selecting a consortium with an immunogenicity of not more than the negative control cannot be determined because the examples do not test the immunogenicity of the consortium bacteria, they only test the immunogenicity of dough comprising the consortium.
The state of the prior art and the level of predictability in the art: The art also teaches that many probiotics do not survive incubation in gastric and intestinal conditions with less than 2 log loss of CFU, confirming the specification’s teaching that there is low predictability in claim 1 step (a) and claim 9 step (1). Caillard et al. (2017; PTO-892) teaches that “their [i.e. probiotic oral supplements] sensitivity to gastric juices, acidic pH and bile, is well known” and cites four references to support this statement (pg. 125 par. bridging cols). Caillard et al. also provided new data testing 16 strains (pg. 125 col. 2 par. 3) in simulated gastric conditions (pH 1.2) for at least 30 minutes (“immersed into 500 mL of sterile Simulated Gastric Fluid (SGF) for 1 h, at 37 °C”, par. bridging pg. 125-126) and simulated intestinal conditions for at least 30 minutes (“After 1 h of experiment, pH medium was raised to 7.0 using sterile KH2PO4 buffer (50 mM), pH 7.0, containing 3 g L-1 of pancreatin… After two hours, viable counts were performed”, par. bridging pg. 125-126). All strains had at least 2 log loss of CFU (i.e. the exponent is two values lower, 100-fold loss) after the experiment, and most strains were completely inactivated. This result shows that the initial “identifying” step is even more unpredictable than suggested by the instant specification (which suggested that a quarter of strains should be identified).
Sieiro et al. (US-20170196918-A1; PTO-892) teaches isolating 27 strains, of which only 8 are able to degrade gliadin [0101], which is a type of gluten protein [0003] (i.e. less than a third of strains can degrade gluten at all, it is not reported whether this decreases by 10-70% as required by steps (b) and (2)).
Therefore, Caillard et al. and Sieiro et al. provide evidence that one of ordinary skill in the art considers testing a small number of strains (~16-27) to be routine. Also, Caillard et al. teaches that the “identifying” or “selecting” part of steps (a) or (1) are expected to fail without undue experimentation, which supports the teachings of the instant specification. Sieiro et al. also teaches that the gluten degradation ability of strains is also unpredictable, which is consistent with the specification’s examples and teachings about the state of the art.
The quantity of experimentation needed to make or use the invention: The standard of an enabling disclosure is not the ability to make and test if the invention works but one of the ability to make and use with a reasonable expectation of success and without undue experimentation. A patent is granted for a completed invention, not the general suggestion of an idea (MPEP 2164.03 and Chiron Corp. v. Genentech Inc., 363 F.3d 1247, 1254, 70 USPQ2d 1321, 1325-26 (Fed. Cir. 2004). The instant specification is not enabling because one cannot follow the guidance presented therein, or within the art at the time of filing, and practice the claimed method without first making a substantial inventive contribution.
The invention requires performing several sequential identification and selection steps, and the art and specification agree that surviving simulated gastrointestinal conditions and having robust proteolytic activity against gluten and the claimed range of gluten-related peptides are rare in probiotics. In fact, the Examples show that none of the consortia chosen meet the selection criteria in step (b) or (2) of selecting or identifying “strains that decrease an initial gluten level of at least 5,000 ppm by 10 to 70%” and none meet the selection criteria of claim 2 of “absence of gluten-derived epitopes (the 12-mer peptide, the 14-mer peptide, the 20-mer peptide and the 33-mer peptide) after 180 min of simulated intestinal digestion” (i.e. 6 hour timepoint). As discussed above, both the evidence from the specification and the art show a very low level of predictability and the examples show that even testing <400 strains, which the art shows is an undue level of experimentation, does not lead to success at using the claimed method.
Therefore, the specification and art demonstrate that one of ordinary skill in the art could not use the method beginning with as two probiotic strains as required by the claims, or even beginning with a larger number that is still a reasonable level of experimentation like the 16-27 strains in Caillard et al. and Sieiro et al., and obtain a consortium meeting all the selection criteria in the claims. The amount of experimentation required for enabling guidance, commensurate in scope with what is claimed, goes beyond what is considered ‘routine' within the art, and constitutes undue further experimentation. Therefore, claims 1-9 are rejected under 35 U.S.C. §112(a) or 35 U.S.C. §112, first paragraph, for failing to meet the enablement requirement. Dependent claims are also rejected because they do not obviate the issues in claims 1, 2, and 9 that were discussed above.
Response to Arguments
The examiner has copied directly from the OCRed copy of the arguments, including any errors that occurred in the OCR process.
Applicant argues (Remarks pg. 12) that (A) Breadth of the claims: “The claimed process is not overly broad and each step can be practiced without undue experimentation. It requires a number of steps that identify probiotic bacteria resistant to acidic gastric conditions and to alk~aline intestinal conditions defined at specific pH ranges, identify those strains that digest gluten, and fiurther identify a narrower subset of strains that digest gluten fr-agments. These steps clearly teach how to make and use the claimed process. Moreover, claim I has been further narrowed to require use of specific bacterial strains: Lactobacillus, Bacillus, Pedliococcus and Wveissella.
In section 25 of the OA, the Examiner asserts that "if all strains or consortia fail to meet the benchmark, then the method has not be successfu". The Examiner's position is respectfully traversed. Enablement pertains to whether thespecification teaches the person skilled in the aar to use the claimed processwithout undue experimentation. Enablement is not a guarantee that practicing the process would yield a successful result. It is not required that the claimed process will identify a bacterial consortium in every sample or from every sou~rce, only that the process itself can be practiced without undue experimentation. The Office has not met its burden of showing that each step of the method could not be easily practiced by those skilled in the art.”
The argument has been carefully considered but is not found persuasive. First, the examiner agrees with the applicant that enablement does not require a guarantee that practicing the process would yield a successful result. However, enablement does require that the method can be used without undue experimentation (see MPEP 2164.01). In this case, the claim is written to have steps that rely on the success of earlier steps. The claim is not a method of performing a set of laboratory tests disclosed in the specification, such as measuring CFU remaining after exposure to gastric conditions, measuring proteinase activity, etc. As applicant stated, the claims require “a number of steps that identify probiotic bacteria resistant to acidic gastric conditions and to alk~aline intestinal conditions defined at specific pH ranges, identify those strains that digest gluten, and fiurther identify a narrower subset of strains that digest gluten fr-agments” (emphasis added). The claim does not require that one begin with bacteria that are already known to have the properties being selected for in the experimental method. One cannot perform the later identifying and combining steps if all bacterial strains under testing have already been eliminated from the group being tested, and in those cases, the method cannot be successfully used. The remaining Wands factors are considered to determine whether, on the whole, the method can be practiced with an amount of experimentation that is reasonable or unreasonable.
Applicant argues (Remarks pg. 12): (B) “The nature of the invention involves a method for identifying pro bioticbacteria that are resistant to gastric and intestinal condition and which can digestgluten and its fragments. It provides step-by-step process for such screening.”
The examiner largely agrees with this characterization, but notes again that the steps in the process require identifying and combining steps that rely on the earlier steps having been successful.
Applicant argues (Remarks pg. 12-13): (C) “The state of the prior art shows that methods for identifying bacteria resistant to gastric and intestinal pH ranges as well as methods for determining protease activity were known. Claim 1 clearly sets for the pH ranges for evaluating bacterial resistance to gastric or intestinal conditions. The selected strain must meet both of these conditions and so would not simply read on a strain resistant to the pH of water.”
The argument has been carefully considered but is not found persuasive. The examiner agrees that the prior art teaches methods for performing the experimental methods for identifying bacteria resistant to gastric and intestinal pH ranges and determining protease activity. However, the claim also requires identifying, selecting, and combining bacteria with these properties. As discussed above, the prior art shows that bacteria with all the required properties are rare (see state of the prior art section beginning par. 36).
The examiner agrees that if one began with a pool of bacteria that are only resistant to the pH of water, then this would not read on the exposure to gastric pH and the method would fail at step (a) because the “identifying” step cannot be performed. However, the examiner notes that being resistant to the pH of water (pH 7) would meet the part of claim 1 step (a) and claim 9 step (1) “exposure to an intestinal pH of 5.5 to 8.5 for at least 30 minutes” as discussed in the rejection above (see par. 17).
Applicant argues (Remarks pg. 13): (D) “The level of skill in the art was high, generally M.D. or Ph.D or post- doctoral level.”
The examiner agrees with this characterization.
Applicant argues (Remarks pg. 13): (E) “The level of predictability in the art was high. The assays used by the inventors were widely accepted.”
The argument has been carefully considered but is not found persuasive. The examiner agrees that the experimental assays were widely accepted. However, the claim also requires identifying, selecting, and combining bacteria with certain claimed properties. Being able to perform the experimental assays is not enough to use the method as claimed. Contrary to applicant’s argument, the level of predictability for performing the method as claimed, including all identifying, selecting, and combining steps was low: “The invention requires performing several sequential selection steps, and the art and specification agree that surviving simulated gastrointestinal conditions and having robust proteolytic activity against gluten and the claimed range of gluten-related peptides are rare in probiotics.” (see par. 40 above)
Applicant argues (Remarks pg. 13): (F) “The amount of direction provided by the inventors is high as evident from the disclosure of strains showing very high peptidase activities on pages 14- 15 of the specification and the experimental work in Examples 1-5 of the specification.”
The argument has been carefully considered but is not found persuasive. The claim is not limited to performing the method on the specific strains identified by the specification; instead, the method can begin with any bacteria in the claimed species as discussed above. It is also noted that the examples in the specification do not perform the method as claimed, for the reasons discussed in the rejection above. The examiner’s position on the direction provided by the specification remains as laid out above.
Applicant argues (Remarks pg. 13): (G) “The inventors provide numerou working examples of the processsteps required by the claims. See Examples 1-5.”
The argument has been carefully considered but is not found persuasive. Examples 1-5 were considered in the rejection above (see par. 18-23). The examiner’s position on the working examples remains as laid out above.
Applicant argues (Remarks pg. 13): (G) “The quantity of experimentation based on the present disclosure is low and could be accomplished by those skilled in the microbiological arts.
The argument has been carefully considered but is not found persuasive. The examiner agrees that the experimental assays could be performed with minimal experimentation. However, the claim also requires identifying, selecting, and combining bacteria with certain claimed properties. As stated above: “The invention requires performing several sequential selection steps, and the art and specification agree that surviving simulated gastrointestinal conditions and having robust proteolytic activity against gluten and the claimed range of gluten-related peptides are rare in probiotics. … Therefore, the specification and art demonstrate that one of ordinary skill in the art could not use the method beginning with as few as two probiotic strains as in the broadest reasonable interpretation of the claims, or even beginning with a larger number that is still a reasonable level of experimentation like the 16 strains in Caillard et al. or the 27 strains in Sieiro et al., and obtain a consortium meeting all the selection criteria in the claims. The amount of experimentation required for enabling guidance, commensurate in scope with what is claimed, goes beyond what is considered ‘routine' within the art, and constitutes undue further experimentation.” (par. 40-41).
The arguments are not persuasive and the claims remain rejected.
Claims 9 remains rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, 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, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim 9 recites “combining at least two of said strains with a first consortium of other probiotic strains having at least 1 U/g peptidase activity for each of PepN, PepI, PepO, PepX and PepQ to form resulting consortium.” Applicant has not pointed out where the amended claim is supported, nor does there appear to be a written description of the claim limitation ‘combining at least 2 strains with some other consortium known to have at least 1U/g peptidase activity for the peptidases’ in the application as filed. The specification measures some peptidase activities for individual strains (Example 2), but it is unclear whether the observed level of activity meets the selection criteria of “at least 1 U/g”, PepQ was not tested, and support has not been found in the specification for combining strains being tested with some other consortium. Accordingly, the newly amended limitation constitutes new matter.
Response to Arguments
Applicant’s arguments did not address this rejection, which was originally presented at FOA par. 52. Therefore, applicant’s arguments are not persuasive.
New Rejection(s)
Claim Rejections - 35 USC § 112(b)
Claims 1-7 and 9-14 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, step (c) (formerly step (4)) has been amended to read “assaying the proteinase activities of the two or more probiotic bacterial strains of (b) to identify at least two probiotic bacterial strains that have an aminopeptidase N (PepN), PepI, PepO, prolyl endopeptidyl peptidase (PEP), PepX and/or PepQ peptidase activity …” The claim requires identifying strains with certain peptidase activities, but the claim never measures the required peptidase activities (it only measures proteinase activity). The instant specification uses the terms “peptidase” and “proteinase” in non-overlapping manners (“peptidase and proteinase activities” [0074]). The specification refers to measuring “Proteinase Activities of Strains Towards Gluten” in step 3 and specifically measuring “Proteinase (cell-envelope-associated proteinase) activity” [0058, emphasis added]. In contrast, the specification refers to “Peptidase Activities of Strains Towards Synthetic Substrates” in step 4 “to assay the cytoplasm peptidase activities,” [0061, emphasis added] which include “General aminopeptidase type N (PepN), proline iminopeptidase (PepI), X-prolyl dipeptidyl aminopeptidase (PepX) activities of the cytoplasmic extracts” [0062]. The claim’s step of “assaying the proteinase activities” does not provide the necessary information for the “identifying” part of step (c) because it measures activity of a completely different set of proteins. Therefore, the claim is incomplete for omitting essential steps, such omission amounting to a gap between the steps. See MPEP § 2172.01. The omitted steps are: measuring the PepN, PepI, PepO, PEP, PepX, and/or PepQ activities. The art cannot remedy this omission because the peptidase activity values are not well known in the art for a representative number of all possible probiotic bacterial strains. The rejection of claim 1 is also a rejection of dependent claims 2-7 and 10, 14 as indefinite because they do not obviate the lack of clarity. Clarification is requested. Claim 11-13 are not rejected because they recite that steps of measuring peptidase activity are performed.
Regarding claims 1 and 2, the claims recite multiple different consortia: “a consortium of probiotic bacterial strains” defined by its peptidase activity in claim 1 (d), “a consortium of (d)” defined by reducing gluten level and degrading the peptides of SEQ ID NOs: 1-4 in claim 1(e), “the consortium of strains” whose properties are not defined that are used for determining gluten hydrolysis in the first step in claim 2, “selecting a consortium” defined by the degradation capacity of gluten in the first step in claim 2, “the consortium of strains” whose properties are not defined that are used for determining immunogenicity in the second step of claim 2, and “selecting a consortium of strains” defined by the level of immunogenicity in the second step of claim 2. Also, both claims require the preamble from claim 1: “A process to identify a consortium of two or more probiotic bacterial strains selected from the group consisting of Lactobacillus, Bacillus, Pediococcus and Weissella for promoting degradation of gluten and gluten-derived peptides”. There is insufficient antecedent basis for the several recitations of “consortium” in the claims. One of ordinary skill in the art would not be able to determine which consortia (if any) are the same, which consortia (if any) are different, and whether the preamble’s intended use is satisfied by identifying any of the consortia, all of the consortia, or only certain consortia. The rejection of claim 1 is also a rejection of dependent claims 2-7 and 10-14 as indefinite because they do not obviate the lack of clarity.
Regarding claim 2, the claim recites “simulated gastrointestinal conditions” and “simulated intestinal digestion”. There is insufficient antecedent basis for these limitations, and the terms do not have accepted definitions in the field at the time of filing because one may choose to simulate different parts of the gastrointestinal conditions such as pH, presence of certain proteins or bile salts, etc. In the interest of compact prosecution, this is interpreted as referring to “exposure to a gastric pH of 1 to 4 for at least 30 minutes” and “exposure to an intestinal pH of 5.5 to 8.5 for at least 30 minutes” from claim 1 step (a).
Regarding claim 3, the claim recites “the gastric conditions”. There is insufficient antecedent basis for this limitation. In the interest of compact prosecution, it is also noted that claim 3 as amended recites that “the gastric conditions” comprise two different incubations (“incubating strains at pH 1-4… and incubating strains at pH 5.5- pH 8.5…”), but the second incubation step was previously an incubation in intestinal conditions instead, and the “exposure to a gastric pH” in claim 1 only incubates at a single pH range.
Regarding claim 4, the claim recites “wherein the activities of peptidases … are determined using…” There is insufficient antecedent basis for a wherein clause limiting a step of determining the activities of peptidases because this step has not been previously recited (note that claim 1 (c) assays proteinase activity instead). If this is intended to be a new step in addition to the steps in the method of claim 1, the claim should be amended to clearly indicate that. For example, claim 2 is one example of clearly indicating that the claim includes additional steps not found in claim 1.
Regarding claim 5, the claim recites “wherein the peptidase activities are determined”. There is insufficient antecedent basis for this term because claim 1 does not recite “the peptidase” and instead recites many different peptidases by name. One of ordinary skill would not be able to determine which peptidase is referenced in claim 5. There is insufficient antecedent basis for a wherein clause limiting a step of determining the activities of peptidases because this step has not been previously recited (note that claim 1 (c) assays proteinase activity instead). If this is intended to be a new step in addition to the steps in the method of claim 1, the claim should be amended to clearly indicate that. For example, claim 2 is one example of clearly indicating that the claim includes additional steps not found in claim 1.
Regarding claim 9, the claim recites “selecting a second consortium with a peptidase activity that degrades all four epitopes”. There is insufficient antecedent basis for the limitation “all four epitopes” because the term epitope has not been previously used. In the interest of compact prosecution, the claim is interpreted as “all four epitopes” referring to SEQ ID NOs: 1-4.
Regarding claims 11-13, these claims also recite “wherein the peptidase activity … is measured.” There is insufficient antecedent basis for a wherein clause limiting a step of determining the activities of peptidases because this step has not been previously recited (note that claim 1 (c) assays proteinase activity instead). If this is intended to be a new step in addition to the steps in the method of claim 1, the claim should be amended to clearly indicate that. For example, claim 2 is one example of clearly indicating that the claim includes additional steps not found in claim 1.
Claim 7 recites “the bacterial strains” but all recitations in claim 1 are “the probiotic bacterial strains.” Claims 10-11 each recite “the suitable substrate” but all recitations in claim 1 are “the suitable peptide substrate.” These differences do not cause antecedent basis issues at this time because there is no other, similar term in claim 1 that could cause ambiguity. However, applicant may wish to amend the dependent claims to exactly match the text of claim 1 in order to avoid the potential for future ambiguity.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1-14 are rejected under 35 U.S.C. 101 because the claimed invention is directed to an abstract idea without significantly more.
All claims but claim 9 recite methods to “identify a consortium of two or more probiotic bacterial strains selected from the group consisting of Lactobacillus, Bacillus, Pediococcus and Weissella for promoting degradation of gluten and gluten-derived peptides”. The claims comprise many different mental steps of “identifying” in claim 1 steps (a)-(c), and also comprise the mental step of “selecting” in claim 1 step (e) and claim 2 because the broadest reasonable interpretation of “selecting” is only a mental selection. The dependent claims also recite these mental steps by depending from claim 1.
Claim 9 recites a method “for producing a consortium of bacteria that reduces an initial gluten level of at least 5,000 ppm to a concentration of hydrolyzed and residual gluten of less than 200 ppm” but where the final step is “selecting a second consortium” rather than producing, mixing, or combining bacteria. Similar to claim 1, claim 9 has several mental steps of “selecting” because the broadest reasonable interpretation of “selecting” is only a mental selection.
This judicial exception is not integrated into a practical application by the non-mental assay and “combination” steps because the intended use of claim 1 and dependent claims is the mental step of identifying, and although claim 9 recites a non-mental step of “producing” this step never actually occurs and the final step is also a mental step of “selecting”. Also, the claims do not use the judicial exception to improve a computer or another piece of technology. The claims do not use the judicial exception in a particular treatment or prophylaxis because the claims do not administer any products to any subjects. The claims do not recite any particular machine that is integral to the claim. The claims do not transform a particular article to a different state or thing; at most the mental steps earlier in the method could be considered used in the step of “combining” strains together, but this does not transform the strains themselves and this combining step does not use the final “selecting” mental step. Instead, the non-mental assay and “combination” steps appear to only generally link the judicial exceptions to the field of use of performing laboratory experimentation on bacteria. Therefore, the additional elements to not integrate the judicial exceptions into a practical application, see also MPEP 2106.04(d).
The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the non-mental assay and “combination” steps simply append well-understood, routine, conventional activities previously known to the industry, specified at a high level of generality, to the judicial exception. Applicant’s arguments admit that “methods for identifying bacteria resistant to gastric and intestinal pH ranges as well as methods for determining protease activity were known” (Remarks pg. 12) and “The assays used by the inventors were widely accepted.” (Remarks pg. 13). MPEP 2106.05.A and the courts are clear that using well known, routine, and conventional methods is not enough to qualify as “significantly more”. Also, the non-mental steps are not considered “significantly more” for the same reasons that they did not integrate the judicial exceptions into a practical application, note the shared relevant considerations in MPEP 2106.05.
Conclusion
No claims are allowed.
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/AMELIA NICOLE DICKENS/Examiner, Art Unit 1645
/DANIEL E KOLKER/Supervisory Patent Examiner, Art Unit 1645