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 .
References to the specification in this action use the paragraph numbers from Pre-Grant Publication US20230042485A1.
Claim Status
The amended claim set filed 4 May 2026 is acknowledged. Claims 1-7, and 10-14 are currently pending. Of those, claims 1-4, 7, 11, and 14 are currently amended, and no claims are new. No claims are withdrawn. Claims 8-9 are cancelled. Claims 1-7, and 10-14 will be examined on the merits herein.
Claim 6 has an amendment marked that was previously presented in the 16 Jan 2026 claim set. Nevertheless, the claims were examined because they could be understood despite the non-compliant amendment.
Applicant is warned that pg. 11 of the Remarks state that claim 1 step (d) is “amended as shown below” but the text in the Remarks differs from the text submitted in the claim set. Examination was based on the claim text submitted in the claims.
Response to Arguments
The Applicants’ arguments filed 4 May 2026 are acknowledged. For clarity, in this action, said arguments will be referred to as “Remarks” and the Non-Final Office Action mailed 2 March 2026 will be referred to as “NFOA.”
Objection(s) and Rejection(s) Withdrawn
The rejection of claim 9 under 35 U.S.C. 112(a) (NFOA par. 63-64) is moot because the claim has been canceled.
The following rejections under 35 U.S.C. 112(b) are withdrawn in view of the claim amendments:
Related to claim 1 step (c) (NFOA par. 68)
Related to claims 1-2 (NFOA par. 69) is withdrawn in part, see maintained part below.
Related to claim 2 (NFOA par 70) is withdrawn in part, see maintained part below.
Related to claim 3 (NFOA par. 71)
Related to claims 4-5 (NFOA par. 72-73)
Related to claim 9 (NFOA par. 74)
Related to claims 11-13 (NFOA par. 75)
The rejection of claims 1-14 under 35 U.S.C. 101 (NFOA par. 77-81) is withdrawn in view of the claim amendments and arguments.
Claim Objections
Claim 1 is objected to because of the following informalities: step (b) states “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 in the presence of 0.02 to 0.6 % w/v pancreatin and 0.05 to 0.6% bile salts for at least 30 minutes”, but grammatically the claim should have a comma instead of a colon. Appropriate correction is required.
Claim 1 is objected to because of the following informalities: step (d) states “produce, isolate, or separate, at least two probiotic bacterial strains”, but comma after “separate” is grammatically unnecessary and should be removed. Appropriate correction is required.
Claim 2 is objected to because of the following informalities: the claim has been amended to define “simulated g:astrointestinal conditions and gastro-intestinal conditions” as being defined in the same way. The claims have a lack of clarity because they use two different terms to refer to the same concept. It is requested that applicant use a single term for this concept throughout the claim to increase clarity and readability. Appropriate correction is required.
Claim 4 is objected to because of the following informalities: the claim has been amended to recite “wherein . Appropriate correction is required.
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(b)
Claims 2 and 6 remain 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 2, the claim recites multiple different consortia: “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”; after amendment this consortium is “the consortium of (e)” as stated in claim 1 step (f) . There is insufficient antecedent basis for the several recitations of “consortium” in claim 2. One of ordinary skill in the art would not be able to determine which consortia (if any) are the same as each other and the consortium of parent claim 1, and which consortia (if any) are different. This rejection of claim 2 is also a rejection of claim 6 because it depends from claim 2 and does not obviate this grounds of rejection.
Regarding claim 2, the claim recites “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 intestinal 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 an intestinal pH of 5.5 to 8.5 for at least 30 minutes” from claim 1 step (a). This rejection of claim 2 is also a rejection of claim 6 because it depends from claim 1 and do not obviate this grounds of rejection.
Response to Arguments
Applicant argues (Remarks pg. 11) that “Claims 1 and 2 were rejected as reciting multiple different consortia and lack of antecedent basis for several recitations of "consortium" and for ambiguous use of this term. This rejection is moot in view of the amendment of claim 1 step ( f) to reference the consortium of step (e) and to reference the consortium of the preamble of claim 1 to the last step (f) of the claim”
This argument has been carefully considered but is not found persuasive. The amendments to claim 1 overcome the part of the rejection related to claim 1, but do not address the multiple ambiguous uses of “consortium” in claim 2. The argument does not point out errors in the rejection above, so it is maintained.
Applicant argues (Remarks pg. 11) that “Claim 2 was rejected as unclear as to the terms "simulated gastrointestinal conditions" and "simulated intestinal digestion". Claim 2 has been amended to describe these conditions by reference to specific pH or other chemical conditions. This basis for rejection cannot be sustained.”
This argument has been carefully considered but is not found persuasive. The amended claim 2 only defines “simulated gastrointestinal conditions and gastro-intestinal conditions”, but does not define “simulated intestinal digestion”. The argument does not point out errors in the rejection above, so it is maintained.
Claim Rejections - 35 USC § 112(a)
Claims 1-7 and 10-14 remain 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. There is insufficient evidence from the specification and art that the method can be used successfully, even with experimentation that goes beyond what the art at the time of filing considers reasonable experimentation.
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 produce, isolate, or separate a consortium of probiotic strains for promoting a degradation of gluten and gluten-derived peptides, comprising performing sequential experiments and producing, isolating, or separating strains based on the results of those experiments. 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 initial “library of at least 10 probiotic bacterial strains [be] selected from the group consisting of Lactobacillus, Bacillus, Pediococcus and Weissella”. In particular, the claims require:
“(b) producing, isolating, or separating 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 in the presence of 0.02 to 0.6 % w/v pancreatin and 0.05 to 0.6% bile salts for at least 30 minutes”.
“(c) assaying proteinase activities of the two or more probiotic bacterial strains retained from (b) and producing, isolating, or separating at least two strains that decrease an initial gluten level of at least 5,000 ppm by 10 to 70%”
“(d) assaying the peptidase activities of the two or more probiotic bacterial strains retained from (c) to produce, isolate, or separate, 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; wherein one unit (U) of activity was defined as the amount of enzyme required to liberate 1 µmol of p-nitroanilide per min under assay conditions”. Note that the assay measures any peptidase activity on any suitable substrate. The broadest reasonable interpretation does not require that PepN, PepI, PepO, PEP, PepX and/or PepQ be measured; it only requires that the produce, isolate, or separate part of the step result in at least two probiotic bacterial strains with having certain levels of those proteins.
“(e) combining the at least two probiotic strains from (d) to produce a consortium of probiotic strains having complementary peptidase activities 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 (f) producing, isolating, or separating from combinations of two or more probiotic strains a consortium of (e) 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%, thereby producing, isolating, or separating a consortium for promoting degradation of gluten and gluten-derived peptides.” Note that this step requires producing the same consortium of (e) which is required to have certain levels of peptidase activity and required to have certain gluten degradation and peptide degradation properties. Note that as in (d), there is no requirement that the peptidases PepN, PepI, PepO, PepX, and PepQ have had their activity measured, the broadest reasonable interpretation requires only that a generic peptidase has been measured.
Claim 2 has additional steps: “determining hydrolysis of gluten during wheat bread digestion by the consortium of strains under simulated gastrointestinal conditions and producing, isolating, or separating 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 producing, isolating, or separating a consortium of with an immunogenicity of not more than the negative control.”
The “producing, isolating, or separating” and “combining” limitations in steps (b-f) 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 produce, isolate, or separate at each step; if all strains or consortia fail to meet the benchmark, then the method has not been successful.
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-b)). 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) (similar to claim 1 step (d)). 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 (d) 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 or cytoplasm… wherein one unit (U) of activity was defined as the amount of enzyme required to liberate 1 µmol of p-nitroanilide per min under assay conditions” as required by claim 1 step (d).
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 “consortium of (e)” is required to have properties related to the assay in step (f). All consortia at least partially hydrolyze the peptides (Figure 3), but the specification does not teach that the “Partially Hydrolyzed” results meet the step (f) 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 (c) and (f) 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 (c) 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. 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) also has a high level of predictability because it only requires providing known bacterial strains.
Claim 1 step (b) 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) with survival after exposure to gastric and intestinal conditions. Therefore, producing, isolating, or separating bacteria with those properties is difficult and unpredictable due to the rarity of bacteria with those properties.
Claim 1 step (c) 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%. Therefore, producing, isolating, or separating bacteria with those properties is very difficult and unpredictable because bacteria with those properties cannot be identified even by the specification’s library, which is much larger than the smallest claimed library size. If the strains are not present in the library, they cannot be produced, isolated, or separated from that library.
Claim 1 step (d) the part of the step of producing, isolating or separating 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. If the strains are not present in the library, they cannot be produced, isolated, or separated from that library. 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 and other, generic peptidases have not been measured.
Claim 1 step (e) 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. Therefore, producing, isolating, or separating bacteria with those properties is very difficult and unpredictable because bacteria with those properties cannot be identified even by the specification’s library, which is much larger than the smallest claimed library size. If the strains are not present in the library, they cannot be produced, isolated, or separated from that library.
Similarly, for claim 1 step (f) the level of predictability for the consortium of (e) 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) 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. Therefore, producing, isolating, or separating bacteria with those properties is very difficult and unpredictable because bacteria with those properties cannot be identified even by the specification’s library, which is much larger than the smallest claimed library size. If the strains are not present in the library, they cannot be produced, isolated, or separated from that library.
Claim 1 step (f) the level of predictability is for the consortium of (e) 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. Therefore, producing, isolating, or separating bacteria with those properties is very difficult and unpredictable because bacteria with those properties cannot be identified even by the specification’s library, which is much larger than the smallest claimed library size. If the strains are not present in the library, they cannot be produced, isolated, or separated from that library.
Claim 2 the level of predictability for the step of producing, isolating, or separating 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 producing, isolating, or separating 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. Therefore, producing, isolating, or separating bacteria with those properties is very difficult and unpredictable because bacteria with those properties cannot be identified even by the specification’s library, which is much larger than the smallest claimed library size.
Claim 2 the level of predictability for producing, isolating, or separating 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 (b). Caillard et al. (2017; made of record in PTO-892 mailed 19 March 2025) 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; made of record in PTO-892 mailed 2 March 2026) 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 claim 1 step (c)).
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 “producing, isolating or separating” part of step (b) is 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 (c) 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. If the strains are not present in the library, they cannot be produced, isolated, or separated from that library.
Therefore, the specification and art demonstrate that one of ordinary skill in the art could not expect to “produce, isolate, or separate a consortium for promoting degradation of gluten and gluten-derived peptides” meeting all the selection criteria required by the claims with a reasonable expectation of success when using the method beginning with as few as ten 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., or even the very large number of <400 strains tested in the specification. 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 1-7 and 10-14 are rejected under 35 U.S.C. §112(a) or 35 U.S.C. §112, first paragraph, for failing to meet the enablement requirement.
Response to Arguments
Applicant argues (Remarks pg. 8) that the rejection cannot be maintained in view of the amendments to claim 1 and to the remarks responding to the Examiner’s arguments starting at section 42 of the NFOA.
This argument has been carefully considered but is not found persuasive. The amendments to claim 1 do not overcome the rejection above, which has been updated to reflect the claim amendments. It is noted that applicant has not pointed out any errors in the rejection of record and is only disputing the arguments.
Applicant argues (Remarks pg. 8, 9) that arguments related to the pH of water are now irrelevant.
The examiner agrees; this line of argument is moot in view of the amendments to claim 1 and it has been removed from the rejection above.
Applicant argues (Remarks pg. 9) that “The primary issue here appears to be that bacteria that could meet all the conditions-resistant to gastrointestinal conditions, digest gluten, and digest gluten fragments--required by claim 1 are rare. However, rarity of a desired species is not the test for enablement. The Examiner's rejection focuses sole on the alleged rarity of bacteria satisfying the conditions required by claim 1 without addressing the actual screening protocol disclosed in the specification or the guidance provided to obtain such bacteria. While the claimed method can produce, isolate, or separate a "rare" subset of bacterial, the claimed subject matter is a defined process for screening, not a broad genus claim attempting to monopolize all such bacterial. Reproducible methods, such as those of claim 1, are generally enabled where the steps can be performed without undue experimentation, even if only a subset of the screened candidate bacteria meet the screening criteria.”
Applicant further argues (Remarks pg. 9) that “The rarity of bacterial meeting the conditions required by claim 1 does not suggest that the process steps of claim 1 are not enabled. One skilled in the art would simply increase the number of bacterial strains screened via the process of claim 1 if a strain meeting all the claim 1 criteria were rare.”
Applicant further argues (Remarks pg. 10) that “The Examiner considers that the amount of direction provided by the inventors is insufficient apparently based on a "rarity" argument which is explained above. Rather, enablement turns on whether the specification teaches a person of ordinary skill in the art to make and use the full scope of the claimed method without undue experimental, MPEP 2164.01(a).”
Applicant further argues (Remarks pg. 10) that “The Applicant notes that claim 1 does not require screening "as few as two probiotic strains", OA, section 61. It imposes no limit on the number of strains screened by the process steps of claim 1. Those skilled in the art would select a suitable number of strains for screening by the process steps of claim 1.”
This argument has been carefully considered but is not found persuasive. Respectfully, the statement that the rejection does not “[address] the actual screening protocol disclosed in the specification or the guidance provided to obtain such bacteria” is inaccurate, see the sections discussing the guidance from the working examples (par. 27-32), the guidance from the other parts of the specification (par. 33), and the direction that the specification provides related to the level of predictability for the different steps of the screening protocol based on the disclosure in the specification (par. 34-43). See also the corresponding sections from the NFOA. As stated above and in the NFOA (par. 15), the issue is not the rarity of the strains per se, the issue is that one cannot produce, isolate, or separate a consortium of bacteria if said bacteria are not present in the initial library: “In other words, to successfully use the method as claimed, there must be strains or consortia to produce, isolate, or separate at each step; if all strains or consortia fail to meet the benchmark, then the method has not been successful.” (par. 26).
For the full scope of the claim to be enabled, the claim must be usable with a reasonable expectation of success with a library of as few as 10 bacterial strains (see claim 1(a) as amended, and par. 24, 49 above). If one of ordinary skill in the art at the time of filing must increase the size of the library to have a reasonable expectation of success, then the full claim scope is not enabled. As stated above (par. 32, 48-49) and in the NFOA (par. 23, 40-41), the specification shows that even the full library of >400 strains tested in the specification is insufficient experimentation to allow one to successfully produce, isolate, or separate the claimed consortium, and that this is greater than the typical level of experimentation in the field at the time of filing (par. 46 and NFOA par. 38). Applicant has not argued or provided counter-evidence to dispute the examiner’s finding of what level of experimentation is considered routine in the art at the time of filing. Therefore, claim 1 cannot be considered a “reproducible method” as argued by applicant because it cannot be performed even by the specification’s experimentation that goes beyond what the field considered routine experimentation. The rejection’s conclusion that undue experimentation is required is maintained.
Applicant argues (Remarks pg. 9-10) that “"'The test is not merely quantitative, since a considerable amount of experimentation is permissible, if it is merely routine, or if the specification in question provides a reasonable amount of guidance with respect to the direction in which the experimentation should proceed."' In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988); MPEP 2164.06. Here, the amount of screening is directed based on specific assays for gluten and gluten fragment digestion and viability assays for intestinal conditions.”
This argument has been carefully considered but is not found persuasive because it does not specifically point out what part(s) of the claims are allegedly routine. The rejection of record argues that producing, isolating, or separating a consortium with the functional characteristics required by the claims cannot be performed with a reasonable expectation of success. The argument does not address whether those steps are routine, so it is not persuasive.
Applicant argues (Remarks pg. 10) that “As previously explained, the specification provides examples of assays useful in the process of claim 1”
This argument has been carefully considered but is not found persuasive. As stated above (par. 32) and in the NFOA (par. 23), the specification does not perform the steps of producing, isolating, or separating a consortium with the functional characteristics required by the claims, including claim 1.
Applicant argues (Remarks pg. 10) that " claim 1 and its dependents are directed to a screening process and are not product claims to rare bacteria.”
This argument has been carefully considered but is not found persuasive. Respectfully, this statement is inaccurate. Claim 1 is a “process to produce, isolate, or separate a consortium of two or more probiotic bacterial strains” and is not only a screening process. See also the “breadth of the claims” section of the rejection above. If the claims were amended to only perform screening assays and to remove references to making consortia of strains based on the results of the assays, then the rejection would be reconsidered in view of that amendment.
New Rejection(s)
Claim Rejections - 35 USC § 112(b)
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 1-7 and 10-14 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) has been amended to read “producing, isolating, or separating; and retaining at least two strains…”. The addition of the semi-colon between separating and retaining renders the scope unclear because a semi-colon is used to separate clauses in a sentence. Therefore, one of ordinary skill in the art would not be able to determine what needs to be produced, isolated, or separated because the semi-colon concludes the idea before the claim defines the object. Text may have been omitted from the claim amendment. If text was not omitted from the amended claim, the examiner believes applicant may have meant to use a comma instead, so that the claim requires that “producing, isolating, or separating, and retaining” all be performed on “at least two strains…” The rejection of claim 1 is also an rejection of dependent claims 2-7 and 10-14 as indefinite because they do not obviate the lack of clarity. In the interest of compact prosecution, in this action, the claim will be interpreted so that “producing, isolating, or separating, and retaining” all be performed on “at least two strains…”
Regarding claim 1, step (d) has been amended to recite “assaying the peptidase activities”, and later recitation that this assaying has the intended use of “to produce, isolate or separate at least two probiotic bacterial strains that have an aminopeptidase N (PepN), PepI, PepO, prolyl endopeptidyl peptidase (PEP), PepX and/or PepQ peptidase activity”. There is insufficient antecedent basis for the first recitation of “the peptidase” in the claim because peptidases had not been previously discussed. Also, a broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 1 recites the broad recitation “peptidase” (generally), and the claim also recites “aminopeptidase N (PepN), PepI, PepO, prolyl endopeptidyl peptidase (PEP), PepX and/or PepQ peptidase activity” which is the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims. The specification does not define how the activity of PepN, PepI, PepO, PEP, PepX, and/or PepQ can be predicted by measuring other types of peptidases other than these proteins, so one of ordinary skill in the art at the time of filing would not be able to determine whether the scope of peptidases being assayed is limited to the narrower scope or, if not, what other peptidases are also included in the claim scope. The rejection of claim 1 is also an rejection of dependent claims 2-3, and 5-7 and 10-14 as indefinite because they do not obviate the lack of clarity. Claim 4 is not included in this grounds of rejection because it determines the activity of specific peptidases. In the interest of compact prosecution, in this action the claim will be interpreted broadly.
Regarding claim 1, step (d) has been amended to recite “assaying the peptidase activities”, and later recitation that the outcome is “to produce, isolate, or separate, identify at least two probiotic bacterial strains that have … peptidase activity of at least 1 U per gram of cells or cytoplasm of the two probiotic bacterial strains on a suitable peptide substrate; wherein one unit (U) of activity was defined as the amount of enzyme required to liberate 1 µmol of p-nitroanilide per min under assay conditions”. A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 1 recites the broad recitation “suitable peptide substrate”, and the claim also recites “liberate… p-nitroanilide” which is the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims. One of ordinary skill in the art at the time of filing would not be able to determine whether the scope of assays and substrates is broad and includes any suitable assay for measuring peptidase activity, or whether the claim is limited by the intended use to only using assays that liberate the substrate p-nitroanilide. The rejection of claim 1 is also an rejection of dependent claims 2-7, 10, and 12-14 as indefinite because they do not obviate the lack of clarity. Claim 11 is not included in this grounds of rejection because it recites a specific assay and substrate. In the interest of compact prosecution, in this action the claim will be interpreted broadly.
Regarding claim 1, steps (e) and (f) have been amended to recite “(e) combining the at least two probiotic strains from (d) to produce a consortium of probiotic bacterial strains having complementary peptidase activities that in aggregate exhibit at least 1U peptidase activity per gram of cells or cytoplasm for each of peptidases PepN, PepI, PepO, PepX and PepQ; and (f) producing, isolating, or separating from combinations of two or more probiotic strains a consortium of (e) 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%, thereby producing, isolating, or separating a consortium for promoting degradation of gluten and gluten-derived peptides.” These claims have two different production steps (“combining the at least two probiotic strains from (d)” and “producing, isolating, or separating from combinations of two or more probiotic strains”, respectively) but they produce the same “consortium of (e)” product.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 1 recites the broad recitation of producing from any generic “combinations of two or more probiotic strains”, and the claim also recites “combining the at least two probiotic strains from (d)” which is the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims. Additionally, one of ordinary skill in the art at the time of filing would not know whether the same product is required to be produced independently twice, or whether a single production of a consortium satisfies both steps (e) and (f). The rejection of claim 1 is also an rejection of dependent claims 2-8 and 10-14 as indefinite because they do not obviate the lack of clarity. In the interest of compact prosecution, in this action the claim will be interpreted broadly as being met by a single production of the consortium.
Regarding claim 5, it recites “wherein the peptidase activities are determined by using viable cells or cytoplasmic extracts thereof in buffered media at pH 6.0 - 9.0 at 35°C-39°C for 1-12 h and the strains with a degradation capacity of all four epitopes of more than 95 % are selected.” However, claim 1 step (d) has been amended to recite “assaying the peptidase activities of the two or more probiotic bacterial strains retained from (c) to produce, isolate, or separate, 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 of at least 1 U per gram of cells or cytoplasm of the two probiotic bacterial strains on a suitable peptide substrate; wherein one unit (U) of activity was defined as the amount of enzyme required to liberate 1 µmol of p-nitroanilide per min under assay conditions”.
There is insufficient antecedent basis for the “peptidase activities” from claim 5 in step (d) of amended parent claim 1 because the claims recite different assays; claim 5 recites “all four epitopes”, but claim 1 step (d) does not define what are the four epitopes that must be used in claim 5. Instead, claim 1 step (d) recites “a suitable peptide substrate” and may also require that the substrate liberate p-nitroanilide. One of ordinary skill in the art at the time of filing would not be able to clearly interpret the required steps of the method, and whether this is a second, independent assaying step not related to claim 1, whether the selection in claim 1(d) occurs based on both assays’ results, or whether step 5 limits the assay of claim 1(d).
Regarding claim 10, it recites “wherein the suitable substrate comprises at least one of…”. There is insufficient antecedent basis for “suitable substrate” because this term was deleted from claim 1 (d). The rejection of claim 10 is also an rejection of dependent claim 11 as indefinite because it does not obviate the lack of clarity.
Regarding claim 11, it has been amended to recite “a
Regarding claim 13, the claim recites “the peptidase activity of at least 1 U per gram of cytoplasmic extract of the two probiotic bacterial strains on a suitable peptide substrate is measured.” This measurement now has antecedent basis in claim 1 step (d) because of the amendment to measure peptidase activity. The term “cytoplasmic extract” in claim 13 does not have antecedent basis in claim 1 step (d); instead, it recites measuring activity using “cells or cytoplasm”. Cytoplasmic extract is not the same as cytoplasm, so the antecedent basis of the assay step in claim 13 is unclear.
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.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
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 of carrying out his invention.
Claims 1-7 and 10-14 are 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.
Regarding claims 1-2, the claim has amended to read “A process to produce, isolate, or separate This rejection of claim 1 is also a rejection of claims 2-7 and 10-14 because they depend from claim 1 and do not obviate this grounds of rejection.
Regarding claim 2, the claim recites incubating bacteria under “simulated gastrointestinal conditions” to measure degradation of gluten and gluten-derived epitopes SEQ ID NOs: 1-4 (first step in claim 2) and “gastro-intestinal conditions” to measure cytokine expression in small intestinal tissue explants (second step in claim 2), and has been amended to recite “wherein said simulated gastrointestinal conditions and gastro-intestinal conditions comprise 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 mins.” Applicant has not pointed out where the amended limitation is supported. Remarks pg. 7 discuss support for other amendments, but not this amendment. The Remarks pg. 7 states that claim 2 has “been amended for clarity as suggested by the Examiner or for consistency with claim 1 as amended. In view of the nature of these amendments no new matter has been added.” However, the NFOA does not suggest adding this text.
The closest support is found at [0018] step 2, which reads “Incubation of the probiotic bacterial strains of step 1) to simulated gastric (pH 1-4) conditions for at least 30 minutes and intestinal conditions (pH 5.5-8.5) for at least 30 minutes and selecting strains with less than 2 log loss of CFU after stimulated gastric and intestinal conditions;” and at step 7, which reads “Determining peptidase activity for the consortium selected in step 6) for the hydrolysis of gluten with a starting concentration of at least 5000 ppm gluten under simulated gastric (pH 1-4) conditions for at least 30 minutes and intestinal conditions (pH 5.5-8.5) for at least 30 minutes and selecting consortium that reduce an initial gluten level of at least 5000 ppm to a concentration of hydrolyzed and residual gluten of less than 200 ppm.” However, neither of these are the steps of claim 2; the specification does not support using these experimental conditions in the completely different assays of claim 2. Therefore, the newly amended claim limitations constitute new matter. This rejection of claim 2 is also a rejection of claim 6 because it depends from claim 2 and does not obviate this grounds of rejection.
Regarding claim 5, the claim recites “wherein the peptidase activities are determined by using viable cells or cytoplasmic extracts thereof in buffered media at pH 6.0 - 9.0 at 35°C-39°C for 1-12 h and the strains with a degradation capacity of all four epitopes of more than 95 % are selected.” After amendment, this has antecedent basis in claim 1 step (d) “(d) assaying the peptidase activities of the two or more probiotic bacterial strains retained from (c) to produce, isolate, or separate, at least two probiotic bacterial strains that have an aminopeptidase N (PepN), PepI, PepO, prolyl endopeptidyl peptidase (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 peptide substrate; wherein one unit (U) of activity was defined as the amount of enzyme required to liberate 1 pmol of p-nitroanilide per min under assay conditions;” So, claim 5 now limits claim 1(d) to selecting strains with both “a degradation capacity of all four epitopes of more than 95 % are selected” (as in claim 5) and “an aminopeptidase N (PepN), PepI, PepO, prolyl endopeptidyl peptidase (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 peptide substrate; wherein one unit (U) of activity was defined as the amount of enzyme required to liberate 1 pmol of p-nitroanilide per min under assay conditions” (as in claim 1(d) originally). Applicant has not pointed out where the amended limitation is supported. Remarks pg. 7 discuss support for other amendments, but does not disclose any support for this amendment to claim 1(d). Support is also not apparent in the specification for a step of selecting based on both benchmarks together. Therefore, claim 5 is new matter due to the change in its antecedent basis.
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to AMELIA N DICKENS whose telephone number is (571)272-0381. The examiner can normally be reached M-F 8:30-4:30 (EDT/EST).
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Samira Jean-Louis can be reached at (571) 270-3503. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/AMELIA NICOLE DICKENS/Examiner, Art Unit 1645
/SAMIRA J JEAN-LOUIS/Supervisory Patent Examiner, Art Unit 1642
Prosecution Insights