DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Applicant’s After Final response filed 8/13/2026 has been received and entered into the case. Claims 3, 4, 9-11, 24, 25 are pending and have been considered on the merits. All arguments and amendments have been considered. It is noted that the Examiner indicated allowable subject matter in the Final Office Action mailed 6/16/2026; however, after further consideration, new rejections have been applied over the claims herein.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 3, 4, 9-11, 24, 25 is/are rejected under 35 U.S.C. 103 as being unpatentable over Study Details | NCT03775499 | Probiotic BL NCC 2705 and Gluten Sensitivity | ClinicalTrials.gov , Record History 12/13/2018 document and 1/7/2019 document in view of Otten B. ( Safety of Bifidobacterium longum NCC 2705 and production of its serpin in patients with celiac disease and non-celiac gluten sensitivity. UEG Week Virtual Symposium 2020, abstract OP174 (https://www.esanum.com/today/posts/probiotic-provides-a-potential-adjuvant-treatment-to-gluten-free-diet, 2/11/2020) and WO2019/129807 (IDS).
The clinical trials document 2018 teaches a trial method wherein individuals having celiac disease are administered Bifidobacterium longum NCC2705, “1 capsule of BL NCC 2705 or placebo will be given twice a day in the morning and in the evening with a meal over 2 periods of 4 days. On day four a single dose of gluten (3g) will be administered and duodenal fluid will be collected in the following hours through a naso-intestinal catheter. The viability of BL NCC 2705, the production of serpin and its effects on gluten digestion and intestinal enzymatic activity will be determined.
Concentration of bacterial Serpin RNA and/or proteins (ng/mL) in duodenal aspirates Measurements via RT-PRC and immuno-assay [Time Frame: 19 sampling over 6h50 hours at visit 2 (day 4) and visit 3 (from day 22 to day 36)]
Concentration of Probiotic BL NCC 2705 (ng/mL) in duodenal aspirates Measurements via PCR [Time Frame: 19 sampling over 6h50 hours at visit 2 (day 4) and visit 3 (from day 22 to day 36)]
Concentration of gluten derived peptides in duodenal aspirates Effect of BL NCC 2705 on gluten digestion based on the amount of gluten peptides detected in duodenal aspirates [Time Frame: 10 sampling over 3h30 at visit 2 (day 4) and visit 3 (from day 22 to day 36)]
Concentration of gluten derived peptides in urine Effect of BL NCC 2705 on gluten digestion based on the amount of gluten peptides detected in urine [Time Frame: 10 sampling over 3h30 at visit 2 (day 4) and visit 3 (from day 22 to day 36)]
Level of elastase (Units/ mL) activity in duodenal aspirates Measurements of proteolytic activity-based assay [Time Frame: 19 sampling over 6h50 hours at visit 2 (day 4) and visit 3 (from day 22 to day 36).”
The clinical trials document 2019 teaches a trial method wherein “individuals having celiac disease are administered 1 capsule of Bifidobacterium longum NCC2705 twice a day in the morning and in the evening with a meal over 2 periods of 4 days.
On day four a single dose of gluten (3g) will be administered and duodenal fluid will be collected in the following hours through a naso-intestinal catheter. The viability of BL NCC 2705, the production of serpin and its effects on gluten digestion and intestinal enzymatic activity will be determined.
Concentration of bacterial Serpin RNA and/or proteins (ng/mL) in duodenal aspirates
Measurements via RT-PRC and immuno-assay
[Time Frame: 19 sampling over 6h50 hours at visit 2 (day 4) and visit 3 (from day 22 to day 36)]
Concentration of Probiotic BL NCC 2705 (ng/mL) in duodenal aspirates
Measurements via PCR
[Time Frame: 19 sampling over 6h50 hours at visit 2 (day 4) and visit 3 (from day 22 to day 36)]
Concentration of gluten derived peptides in duodenal aspirates
Effect of BL NCC 2705 on gluten digestion based on the amount of gluten peptides detected in duodenal aspirates
[Time Frame: 10 sampling over 3h30 at visit 2 (day 4) and visit 3 (from day 22 to day 36)]
Concentration of gluten derived peptides in urine
Effect of BL NCC 2705 on gluten digestion based on the amount of gluten peptides detected in urine
[Time Frame: 10 sampling over 3h30 at visit 2 (day 4) and visit 3 (from day 22 to day 36)]
Level of elastase (Units/ mL) activity in duodenal aspirates
Measurements of proteolytic activity-based assay
[Time Frame: 19 sampling over 6h50 hours at visit 2 (day 4) and visit 3 (from day 22 to day 36)
Thus, the above references teach a method of administering to an individual having celiac disease a composition comprising an amount of Bifidobacterium longum NCC2705 twice a day in the morning and in the evening with a meal. Glutenasic duodenal activity and duodenal serpin protein concentrations are measured after at least 3 days, i.e. 4 days, after administration of the composition, and are sampled over a period of 6h50 hours at visit 2 (on day 4), therefore meeting applicants limitation of “measured from the administration of the gluten challenge to 370 minutes after the administration of the gluten challenge” of claims 3, and 25, and meeting “measured after the administration of the gluten challenge” of claim 24.
Regarding claims 9 and 10, the composition is in the form of a dietary supplement in capsule form.
The references do not teach the amount of reduction of glutenasic activity or the increase in serpin concentration and is silent as to the effective amount of B. longum.
Otten teaches that B. longum NCC2705 has been shown to ameliorate gluten immunopathology though the production of serpin in the mouse model of celiac disease. Otten teaches the administration of B. longum NCC2705 to celiac patients and find that after intake of the probiotics (on the test day), B. longum NCC2705 was detected in the duodenal aspirates and serpin concentrations increased by 36%. Thus, the probiotic strain has use as an adjuvant treatment to gluten-free diet to protect from accidental gluten intake (p. 2, whole page).
WO’807 teaches a method comprising administering a composition comprising a therapeutically effective amount serpin protein producing B. longum strain CNCM I-2628 (NCC2705) to an individual in need thereof, wherein said individual has celiac disease and gluten-related/gluten-sensitivity disorders triggered by gluten (p. 1, lines 6-11, 21-p. 2, lines 1-6, p. 4, lines 29-31, p. 9, lines 26-p. 12, whole page). Celiac disease is triggered by the digestion of wheat gluten and other cereal proteins from rye and barley, for example (p. 1, lines 24-25). B. longum CNCM I-2618 is disclosed to be used in the treatment or prevention of conditions related to gluten sensitivity or involving reduced activity of serine protease inhibitors (p. 9, lines 26-28) including specifically celiac disease (p. 10, lines 2, 6, 7). Serine protease inhibitors are known to play a role in gluten-related disorders as having potent inhibitory capacity of elastases and proteinases and having a role in celiac disease by inhibiting transglutaminase 2, thus inhibiting deamidation of a 33-mer gliadin peptide (this activity is in itself glutenasic activity), which is a trigger of the adaptive immune response in celiac disease. The serpin protein of B. longum NCC2705 display similar antiprotease activity (p. 2, lines 10-30).
WO’807 teaches that “Clinical evidence shows class Il human leukocyte antigens (HLA-DQII), which strongly relate with celiac disease pathology, are expressed in about 95% of celiac disease patients. In the intestinal lumen, gluten proteins are partially digested, forming proteolytic-resistant 33-mer gluten peptides. After crossing the small intestinal barrier, they are deamidated by transglutaminase 2 (TG2) with negative charges (Sollid, 2000, Annual review of immunology, 18(1), 53-81), which then bind to the positively charged binding sites of HLA-DQ2.5/8 (Dieterich et al., 1997, Nature medicine, 3(7), 797-801). HLA-DQ2.5/8 displaying those specific gluten peptides signals to helper T cells and other immune cells causing further damage in the small intestine. Antibodies against gluten proteins and autoantibodies to connective tissue components (TG2) also associated with celiac disease progression (Alaedini & Green, 2005, Annals of internal medicine, 142(4), 289-298)” (p. 10, lines 19-28).
WO’807 teaches testing NCC2705 in animal models which were sensitized and then challenged with gluten (same as described in McCarville 2017). The strain is administered during the challenge at a dose of 1x109 CFU per day and intestinal content is collected to measure glutenasic activity (elastase activity, p. 15-16, Ex. 2). They find that the strain inhibits glutenasic activity and increases serpin concentration (see Fig. 1 and 2). According to Fig, 2, the elastase activity is reduced by at least 40% when administering the frozen and spray dried NCC2705 compared to control.
Regarding claim 4, WO’807 teaches that gluten contains the cytotoxic protein gliadin as well as other proteins/peptides which contribute to symptoms of gluten-related disorders including celiac disease. Serine protease inhibitors (serpins) have been shown to have potent inhibitory role in gluten-related disorders including potent antiprotease activity and B. longum subsp longum NCC2705 contains serpins having antiprotease activity and protect against proteases in the GI tract, which improve gluten induced pathophysiology in the mouse model of gluten sensitivity and thus is a solution for gluten related disorders (p. 2, lines 2-21, 27-31, p. 3, lines 1-6, Ex. 2 p. 15-16).
Regarding claims 9 and 10, WO’807 teach the composition comprising B. longum strain CNCM I-2628 (NCC2705) to be in the form of a food, medical food, nutritional supplement or pharmaceutical composition, a powder, a tablet, a capsule, and a lozenge (p. 4, lines 8-31, p. 5, lines 21-30, p. 7, lines 9-10).
Regarding claim 11, the composition comprises between 106-1010 cfu of B. longum NCC2705 per dose (p. 7, lines 20-23). Further, the reference teaches that the ideal dose will depend on the subject to be treated, which will vary but can be easily determined by those of skill in the art.
The claimed invention is drawn to a single step of administering a composition comprising therapeutically effective amount of a serpin producing B. longum strain CNCM I-2628 (NCC2705) to an individual in need, wherein said individual in need thereof has celiac disease.
WO’807 teaches the single method step of administering a composition comprising therapeutically effective amount of a serpin producing B. longum strain CNCM I-2628 (NCC2705) to an individual in need (those having gluten-related disorders), wherein said individual in need thereof has celiac disease. The reference teaches that serine protease inhibitors (serpins) have been shown to have potent inhibitory role in gluten-related disorders including potent antiprotease activity and B. longum subsp longum NCC2705 contains serpins having antiprotease activity and protect against proteases in the GI tract, which improve gluten induced pathophysiology and thus is a solution for gluten related disorders (p. 2, lines 2-21, 27-31, p. 3, lines 1-6, Ex. 2 p. 15-16). It is important to note that applicants state that the presence of serpin in the duodenum may confer advantageous properties such as reduced digestion of gluten by reduction of gluten-related proteolytic activity (0133, 0135).
While the cited reference does not teach that their composition is used in a method of inhibiting digestion of gluten, the intended use of the claimed composition does not patentably distinguish the composition, per se, since such undisclosed use is inherent in the reference composition. In order to be limiting, the intended use must create a structural difference between the claimed composition and the composition of the prior art. In the instant case, the intended use fails to create a structural difference, thus, the intended use is not limiting. Please note that when applicant claims a composition in terms of function, and the composition of the prior art appears to be the same, the Examiner may make rejections under both 35 U.S.C 102 and 103 (MPEP 2112). Moreover, the claimed function must be inherent to the reference composition. The discovery of a previously unappreciated property of a prior art composition, or of a scientific explanation for the prior art’s functioning, does not render the old composition patentably new. Thus, the claiming of a new use, functions or unknown property which is inherently present in the prior art does not necessarily make the claim patentable. (MPEP 2112)
II. INHERENT FEATURE NEED NOT BE RECOGNIZED AT THE TIME OF THE INVENTION
There is no requirement that a person of ordinary skill in the art would have recognized the inherent disclosure at the time of invention, but only that the subject matter is in fact inherent in the prior art reference. Schering Corp. v. Geneva Pharm. Inc., 339 F.3d 1373, 1377, 67 USPQ2d 1664, 1668 (Fed. Cir. 2003) (rejecting the contention that inherent anticipation requires recognition by a person of ordinary skill in the art before the critical date and allowing expert testimony with respect to post-critical date clinical trials to show inherency); see also Toro Co. v. Deere & Co., 355 F.3d 1313, 1320, 69 USPQ2d 1584, 1590 (Fed. Cir. 2004) ("[T]he fact that a characteristic is a necessary feature or result of a prior-art embodiment (that is itself sufficiently described and enabled) is enough for inherent anticipation, even if that fact was unknown at the time of the prior invention."); Abbott Labs v. Geneva Pharms., Inc., 182 F.3d 1315, 1319, 51 USPQ2d 1307, 1310 (Fed.Cir.1999) ("If a product that is offered for sale inherently possesses each of the limitations of the claims, then the invention is on sale, whether or not the parties to the transaction recognize that the product possesses the claimed characteristics."); Atlas Powder Co. v. IRECO, Inc., 190 F.3d 1342, 1348-49, 51 USPQ2d 1943, 1947 (Fed. Cir. 1999) ("Because ‘sufficient aeration’ was inherent in the prior art, it is irrelevant that the prior art did not recognize the key aspect of [the] invention.... An inherent structure, composition, or function is not necessarily known."); SmithKline Beecham Corp. v. Apotex Corp., 403 F.3d 1331, 1343-44, 74 USPQ2d 1398, 1406-07 (Fed. Cir. 2005) (holding that a prior art patent to an anhydrous form of a compound "inherently" anticipated the claimed hemihydrate form of the compound because practicing the process in the prior art to manufacture the anhydrous compound "inherently results in at least trace amounts of" the claimed hemihydrate even if the prior art did not discuss or recognize the hemihydrate); In re Omeprazole Patent Litigation, 483 F.3d 1364, 1373, 82 USPQ2d 1643, 1650 (Fed. Cir. 2007) (The court noted that although the inventors may not have recognized that a characteristic of the ingredients in the prior art method resulted in an in situ formation of a separating layer, the in situ formation was nevertheless inherent. "The record shows formation of the in situ separating layer in the prior art even though that process was not recognized at the time. The new realization alone does not render that necessary [sic] prior art patentable.").
Further, applicants’ amendments drawn to “wherein the administering of the composition reduces duodenal glutenasic activity in the individual with celiac disease by at least 40%” and “wherein administration of the composition increases serpin concentration in the individual with celiac disease by at least 40%” are taken to necessarily be happening when administering the same composition (in the claimed therapeutically effective amount demonstrated by WO807) to the same patient population, i.e. a result on the process step of administering. The whereby clause in a method claim is not given weight when it simply expresses the intended result of a process step positively recited.’" Id. (quoting Minton v. Nat’l Ass’n of Securities Dealers, Inc., 336 F.3d 1373, 1381, 67 USPQ2d. 1614, 1620 (Fed. Cir. 2003)). The only method step is administering, and thus the reduction of activity and increase in serpin concentration are only intended results of administering the composition, as well as a function of the preparation. The method of WO’807 is drawn to the same method as claimed, i.e. a B. longum CNCM I-2628 (NCC2705) composition administered to the same celiac subjects. Thus, it is the Examiners position that these results are inherent to the administration step taught by WO’807. One would necessarily expect to achieve the same results when practicing the method of WO’807, which is the same as applicants claimed method.
MPEP 2112 Requirements of Rejection Based on Inherency; Burden of Proof [R-08.2012]
The express, implicit, and inherent disclosures of a prior art reference may be relied upon in the rejection of claims under 35 U.S.C. 102 and 103. “The inherent teaching of a prior art reference, a question of fact, arises both in the context of anticipation and obviousness.” In re Napier, 55 F.3d 610, 613, 34 USPQ2d 1782, 1784 (Fed. Cir. 1995) (affirmed a 35 U.5.C. 103 rejection based in part on inherent disclosure in one of the references). See also In re Grasselli, 713 F.2d 731, 739, 218 USPQ 769, 775 (Fed. Cir. 1983).
Thus, before the effective filing date of the claimed invention, a phosita would have a reasonable expectation of successfully reducing glutenasic activity and increasing serpin concentration in an individual having celiac disease when administering NCC 2705 as taught by the clinical trials references, Otten, and in therapeutically effective amounts taught by WO’807 in light of the teachings of these prior art references. Further, the references teach measuring the activity and concentrations after a gluten challenge and thus methods to determine the efficacy of serpin producing bacteria to reduce glutenasic activity and measure concentrations of serpin in duodenal aspirates were known and practiced by the prior art references of record, and thus would have been obvious to a phosita before the effective filing of the claimed invention.
Claim(s) 3, 4, 9-11, 24, 25 is/are rejected under 35 U.S.C. 103 as being unpatentable over Study Details | NCT03775499 | Probiotic BL NCC 2705 and Gluten Sensitivity | ClinicalTrials.gov , Record History 12/13/2018 document and 1/7/2019 document in view of Otten B. ( Safety of Bifidobacterium longum NCC 2705 and production of its serpin in patients with celiac disease and non-celiac gluten sensitivity. UEG Week Virtual Symposium 2020, abstract OP174 (https://www.esanum.com/today/posts/probiotic-provides-a-potential-adjuvant-treatment-to-gluten-free-diet, 2/11/2020) McCarville (Appl. And Env. Microb., 2017, IDS) in view of WO2019/129807.
The clinical trials document 2018 teaches a trial method wherein individuals having celiac disease are administered Bifidobacterium longum NCC2705, “1 capsule of BL NCC 2705 or placebo will be given twice a day in the morning and in the evening with a meal over 2 periods of 4 days. On day four a single dose of gluten (3g) will be administered and duodenal fluid will be collected in the following hours through a naso-intestinal catheter. The viability of BL NCC 2705, the production of serpin and its effects on gluten digestion and intestinal enzymatic activity will be determined.
Concentration of bacterial Serpin RNA and/or proteins (ng/mL) in duodenal aspirates Measurements via RT-PRC and immuno-assay [Time Frame: 19 sampling over 6h50 hours at visit 2 (day 4) and visit 3 (from day 22 to day 36)]
Concentration of Probiotic BL NCC 2705 (ng/mL) in duodenal aspirates Measurements via PCR [Time Frame: 19 sampling over 6h50 hours at visit 2 (day 4) and visit 3 (from day 22 to day 36)]
Concentration of gluten derived peptides in duodenal aspirates Effect of BL NCC 2705 on gluten digestion based on the amount of gluten peptides detected in duodenal aspirates [Time Frame: 10 sampling over 3h30 at visit 2 (day 4) and visit 3 (from day 22 to day 36)]
Concentration of gluten derived peptides in urine Effect of BL NCC 2705 on gluten digestion based on the amount of gluten peptides detected in urine [Time Frame: 10 sampling over 3h30 at visit 2 (day 4) and visit 3 (from day 22 to day 36)]
Level of elastase (Units/ mL) activity in duodenal aspirates Measurements of proteolytic activity-based assay [Time Frame: 19 sampling over 6h50 hours at visit 2 (day 4) and visit 3 (from day 22 to day 36).”
The clinical trials document 2019 teaches a trial method wherein “individuals having celiac disease are administered 1 capsule of Bifidobacterium longum NCC2705 twice a day in the morning and in the evening with a meal over 2 periods of 4 days.
On day four a single dose of gluten (3g) will be administered and duodenal fluid will be collected in the following hours through a naso-intestinal catheter. The viability of BL NCC 2705, the production of serpin and its effects on gluten digestion and intestinal enzymatic activity will be determined.
Concentration of bacterial Serpin RNA and/or proteins (ng/mL) in duodenal aspirates
Measurements via RT-PRC and immuno-assay
[Time Frame: 19 sampling over 6h50 hours at visit 2 (day 4) and visit 3 (from day 22 to day 36)]
Concentration of Probiotic BL NCC 2705 (ng/mL) in duodenal aspirates
Measurements via PCR
[Time Frame: 19 sampling over 6h50 hours at visit 2 (day 4) and visit 3 (from day 22 to day 36)]
Concentration of gluten derived peptides in duodenal aspirates
Effect of BL NCC 2705 on gluten digestion based on the amount of gluten peptides detected in duodenal aspirates
[Time Frame: 10 sampling over 3h30 at visit 2 (day 4) and visit 3 (from day 22 to day 36)]
Concentration of gluten derived peptides in urine
Effect of BL NCC 2705 on gluten digestion based on the amount of gluten peptides detected in urine
[Time Frame: 10 sampling over 3h30 at visit 2 (day 4) and visit 3 (from day 22 to day 36)]
Level of elastase (Units/ mL) activity in duodenal aspirates
Measurements of proteolytic activity-based assay
[Time Frame: 19 sampling over 6h50 hours at visit 2 (day 4) and visit 3 (from day 22 to day 36)
Thus, the above references teach a method of administering to an individual having celiac disease a composition comprising an amount of Bifidobacterium longum NCC2705 twice a day in the morning and in the evening with a meal. Glutenasic duodenal activity and duodenal serpin protein concentrations are measured after at least 3 days, i.e. 4 days, after administration of the composition, and are sampled over a period of 6h50 hours at visit 2 (on day 4), therefore meeting applicants limitation of “measured from the administration of the gluten challenge to 370 minutes after the administration of the gluten challenge” of claims 3, and 25, and meeting “measured after the administration of the gluten challenge” of claim 24.
Regarding claims 9 and 10, the composition is in the form of a dietary supplement in capsule form.
The references do not teach the amount of reduction of glutenasic activity or the increase in serpin concentration and is silent as to the effective amount of B. longum.
Otten teaches that B. longum NCC2705 has been shown to ameliorate gluten immunopathology though the production of serpin in the mouse model of celiac disease. Otten teaches the administration of B. longum NCC2705 to celiac patients and find that after intake of the probiotics (on the test day), B. longum NCC2705 was detected in the duodenal aspirates and serpin concentrations increased by 36%. Thus, the probiotic strain has use as an adjuvant treatment to gluten-free diet to protect from accidental gluten intake (p. 2, whole page).
McCarville teach a method of treating gluten/gliadin-related immunopathology comprising orally administering the serpin producing Bifidobacterium longum strain NCC2705 to gliadin-sensitized NOD/DQ8 mouse model of gluten sensitivity/celiac disease (abstract, p. 2, last parag.-p. 3). McCarville discloses “We have previously shown that expression of the human serine protease inhibitor (serpin) elafin is decreased in the duodenum of patients with active CeD (celiac disease). Recombinant Lactococcus lactis expressing elafin (L. lactis-elafin) has been shown (i) to be protective in several murine colitis models and (ii) to prevent gluten immunopathology in the NOD/DQ8 mouse model of gluten sensitivity…Although eukaryotic serpins such as elafin are known to possess anti-inflammatory properties, bacterially produced serpins have not been explored for their therapeutic capacity in vivo. The infant-derived commensal probiotic strain Bifidobacterium longum NCC2705 (B. longum srp+) produces a serpin (Srp) encoded by the BL0108 (srp) gene in a nonconstitutive manner. Expression of srp is induced in the murine intestinal tract, and Srp may exhibit anti-inflammatory properties as it inhibits both pancreatic elastase and neutrophilic elastase in vitro. We tested the hypothesis that administration of the commensal B. longum srp+ prevents immunopathology in the NOD/DQ8 mouse model of gluten sensitivity.
We show that both the wild-type B. longum srp+ strain and a recombinant strain constitutively expressing srp [B. longum srp(Con)] prevent gliadin-induced immunopathology in NOD/DQ8 mice, whereas an srp knockout strain (B. longum Δsrp) does not. These results clearly suggest that the beneficial effect of B. longum srp+ is mediated by Srp” (p. 2, 1st and 2nd full parag.).
McCarville teach that in gliadin sensitized and then challenged (with gliadin 3x/week for 2 weeks) mice, the administration of 109 CFU of the serpin producing strain NC2705 daily, prevented inflammation induced by gliadin and effectively inhibit serine proteases (elastase) in the mouse model (Fig. 2) and protected mice from developing gliadin-induced immunopathology (Fig. 1-3); therefore, having immunomodulating capacity, reducing glutenasic activity treating gastrointestinal inflammatory conditions and gluten-related disorders (p. 2, Results section-p. 3, whole page, Fig. 1, 2, p. 6, last parag.-p. 9, p. 10, Mucosal delivery section).
The claimed invention is drawn to a single method step of administering a composition comprising therapeutically effective amount of a serpin producing B. longum strain CNCM I-2628 (NCC2705) to an individual in need, wherein said individual in need thereof has celiac disease.
McCarville teaches the single method step of administering a composition comprising therapeutically effective amount of a serpin producing B. longum strain CNCM I-2628 (NCC2705) to an individual in need (those having gluten-related disorders), wherein said individual in need thereof is a celiac disease model mouse. The reference teaches that serine protease inhibitors (serpins) have been shown to have potent inhibitory role in gluten-related disorders including potent antiprotease activity and teach that the administration of the serpin producing strain NC2705 to a gluten-sensitive mouse model prevented inflammation induced by gliadin and effectively inhibit serine proteases (elastase) in the mouse model and protected mice from developing gliadin-induced immunopathology; therefore, having immunomodulating capacity treating gastrointestinal inflammatory conditions and gluten-related disorders.
While the cited reference does not teach that their composition is used in a method of inhibiting digestion of gluten, the intended use of the claimed composition does not patentably distinguish the composition, per se, since such undisclosed use is inherent in the reference composition. In order to be limiting, the intended use must create a structural difference between the claimed composition and the composition of the prior art. In the instant case, the intended use fails to create a structural difference, thus, the intended use is not limiting. Please note that when applicant claims a composition in terms of function, and the composition of the prior art appears to be the same, the Examiner may make rejections under both 35 U.S.C 102 and 103 (MPEP 2112). Moreover, the claimed function must be inherent to the reference composition. The discovery of a previously unappreciated property of a prior art composition, or of a scientific explanation for the prior art’s functioning, does not render the old composition patentably new. Thus, the claiming of a new use, functions or unknown property which is inherently present in the prior art does not necessarily make the claim patentable. (MPEP 2112)
II. INHERENT FEATURE NEED NOT BE RECOGNIZED AT THE TIME OF THE INVENTION
There is no requirement that a person of ordinary skill in the art would have recognized the inherent disclosure at the time of invention, but only that the subject matter is in fact inherent in the prior art reference. Schering Corp. v. Geneva Pharm. Inc., 339 F.3d 1373, 1377, 67 USPQ2d 1664, 1668 (Fed. Cir. 2003) (rejecting the contention that inherent anticipation requires recognition by a person of ordinary skill in the art before the critical date and allowing expert testimony with respect to post-critical date clinical trials to show inherency); see also Toro Co. v. Deere & Co., 355 F.3d 1313, 1320, 69 USPQ2d 1584, 1590 (Fed. Cir. 2004) ("[T]he fact that a characteristic is a necessary feature or result of a prior-art embodiment (that is itself sufficiently described and enabled) is enough for inherent anticipation, even if that fact was unknown at the time of the prior invention."); Abbott Labs v. Geneva Pharms., Inc., 182 F.3d 1315, 1319, 51 USPQ2d 1307, 1310 (Fed.Cir.1999) ("If a product that is offered for sale inherently possesses each of the limitations of the claims, then the invention is on sale, whether or not the parties to the transaction recognize that the product possesses the claimed characteristics."); Atlas Powder Co. v. IRECO, Inc., 190 F.3d 1342, 1348-49, 51 USPQ2d 1943, 1947 (Fed. Cir. 1999) ("Because ‘sufficient aeration’ was inherent in the prior art, it is irrelevant that the prior art did not recognize the key aspect of [the] invention.... An inherent structure, composition, or function is not necessarily known."); SmithKline Beecham Corp. v. Apotex Corp., 403 F.3d 1331, 1343-44, 74 USPQ2d 1398, 1406-07 (Fed. Cir. 2005) (holding that a prior art patent to an anhydrous form of a compound "inherently" anticipated the claimed hemihydrate form of the compound because practicing the process in the prior art to manufacture the anhydrous compound "inherently results in at least trace amounts of" the claimed hemihydrate even if the prior art did not discuss or recognize the hemihydrate); In re Omeprazole Patent Litigation, 483 F.3d 1364, 1373, 82 USPQ2d 1643, 1650 (Fed. Cir. 2007) (The court noted that although the inventors may not have recognized that a characteristic of the ingredients in the prior art method resulted in an in situ formation of a separating layer, the in situ formation was nevertheless inherent. "The record shows formation of the in situ separating layer in the prior art even though that process was not recognized at the time. The new realization alone does not render that necessary [sic] prior art patentable.").
WO’807 teaches a method comprising administering a composition comprising a therapeutically effective amount serpin protein producing B. longum strain CNCM I-2628 (NCC2705) to an individual in need thereof, wherein said individual has celiac disease and gluten-related/gluten-sensitivity disorders triggered by gluten (p. 1, lines 6-11, 21-p. 2, lines 1-6, p. 4, lines 29-31, p. 9, lines 26-p. 12, whole page). Celiac disease is triggered by the digestion of wheat gluten and other cereal proteins from rye and barley, for example (p. 1, lines 24-25). B. longum CNCM I-2618 is disclosed to be used in the treatment or prevention of conditions related to gluten sensitivity or involving reduced activity of serine protease inhibitors (p. 9, lines 26-28) including specifically celiac disease (p. 10, lines 2, 6, 7). Serine protease inhibitors are known to play a role in gluten-related disorders as having potent inhibitory capacity of elastases and proteinases and having a role in celiac disease by inhibiting transglutaminase 2, thus inhibiting deamidation of a 33-mer gliadin peptide (this activity is in itself glutenasic activity), which is a trigger of the adaptive immune response in celiac disease. The serpin protein of B. longum NCC2705 display similar antiprotease activity (p. 2, lines 10-30).
WO’807 teaches that “Clinical evidence shows class Il human leukocyte antigens (HLA-DQII), which strongly relate with celiac disease pathology, are expressed in about 95% of celiac disease patients. In the intestinal lumen, gluten proteins are partially digested, forming proteolytic-resistant 33-mer gluten peptides. After crossing the small intestinal barrier, they are deamidated by transglutaminase 2 (TG2) with negative charges (Sollid, 2000, Annual review of immunology, 18(1), 53-81), which then bind to the positively charged binding sites of HLA-DQ2.5/8 (Dieterich et al., 1997, Nature medicine, 3(7), 797-801). HLA-DQ2.5/8 displaying those specific gluten peptides signals to helper T cells and other immune cells causing further damage in the small intestine. Antibodies against gluten proteins and autoantibodies to connective tissue components (TG2) also associated with celiac disease progression (Alaedini & Green, 2005, Annals of internal medicine, 142(4), 289-298)” (p. 10, lines 19-28).
WO’807 teaches testing NCC2705 in animal models which were sensitized and then challenged with gluten (same as described in McCarville 2017). The strain is administered during the challenge at a dose of 1x109 CFU per day and intestinal content is collected to measure glutenasic activity (elastase activity, p. 15-16, Ex. 2). They find that the strain inhibits glutenasic activity and increases serpin concentration (see Fig. 1 and 2). According to Fig, 2, the elastase activity is reduced by at least 40% when administering the frozen and spray dried NCC2705 compared to control.
Regarding claim 4, WO’807 teaches that gluten contains the cytotoxic protein gliadin as well as other proteins/peptides which contribute to symptoms of gluten-related disorders including celiac disease. Serine protease inhibitors (serpins) have been shown to have potent inhibitory role in gluten-related disorders including potent antiprotease activity and B. longum subsp longum NCC2705 contains serpins having antiprotease activity and protect against proteases in the GI tract, which improve gluten induced pathophysiology in the mouse model of gluten sensitivity and thus is a solution for gluten related disorders (p. 2, lines 2-21, 27-31, p. 3, lines 1-6, Ex. 2 p. 15-16).
Regarding claims 9 and 10, WO’807 teach the composition comprising B. longum strain CNCM I-2628 (NCC2705) to be in the form of a food, medical food, nutritional supplement or pharmaceutical composition, a powder, a tablet, a capsule, and a lozenge (p. 4, lines 8-31, p. 5, lines 21-30, p. 7, lines 9-10).
Regarding claim 11, the composition comprises between 106-1010 cfu of B. longum NCC2705 per dose (p. 7, lines 20-23). Further, the reference teaches that the ideal dose will depend on the subject to be treated, which will vary but can be easily determined by those of skill in the art.
Further, applicants’ amendments drawn to “wherein the administering of the composition reduces duodenal glutenasic activity in the individual with celiac disease by at least 40%” and “wherein administration of the composition increases serpin concentration in the individual with celiac disease by at least 40%” are taken to necessarily be happening when administering the same composition (in the claimed therapeutically effective amount demonstrated by WO807) to the same patient population, i.e. a result on the process step of administering. The whereby clause in a method claim is not given weight when it simply expresses the intended result of a process step positively recited.’" Id. (quoting Minton v. Nat’l Ass’n of Securities Dealers, Inc., 336 F.3d 1373, 1381, 67 USPQ2d. 1614, 1620 (Fed. Cir. 2003)). The only method step is administering, and thus the reduction of activity and increase in serpin concentration are only intended results of administering the composition, as well as a function of the preparation. The method of WO’807 is drawn to the same method as claimed, i.e. a B. longum CNCM I-2628 (NCC2705) composition administered to the same celiac subjects. Thus, it is the Examiners position that these results are inherent to the administration step taught by WO’807. One would necessarily expect to achieve the same results when practicing the method of WO’807, which is the same as applicants claimed method.
MPEP 2112 Requirements of Rejection Based on Inherency; Burden of Proof [R-08.2012]
The express, implicit, and inherent disclosures of a prior art reference may be relied upon in the rejection of claims under 35 U.S.C. 102 and 103. “The inherent teaching of a prior art reference, a question of fact, arises both in the context of anticipation and obviousness.” In re Napier, 55 F.3d 610, 613, 34 USPQ2d 1782, 1784 (Fed. Cir. 1995) (affirmed a 35 U.5.C. 103 rejection based in part on inherent disclosure in one of the references). See also In re Grasselli, 713 F.2d 731, 739, 218 USPQ 769, 775 (Fed. Cir. 1983).
Thus, before the effective filing date of the claimed invention, a phosita would have a reasonable expectation of successfully reducing glutenasic activity and increasing serpin concentration in an individual having celiac disease when administering NCC 2705 as taught by the clinical trials references, Otten, McCarville, and in therapeutically effective amounts taught by WO’807 in light of the teachings of these prior art references. Further, the references teach measuring the activity and concentrations after a gluten challenge and thus methods to determine the efficacy of serpin producing bacteria to reduce glutenasic activity and measure concentrations of serpin in duodenal aspirates were known and practiced by the prior art references of record and thus would have been obvious to a phosita before the effective filing of the claimed invention.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 3, 4, 9-11, 24, 25 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 5, 6 of U.S. Patent No. 11590181 in view of Study Details | NCT03775499 | Probiotic BL NCC 2705 and Gluten Sensitivity | ClinicalTrials.gov , Record History 12/13/2018 document and 1/7/2019 document in view of Otten B. ( Safety of Bifidobacterium longum NCC 2705 and production of its serpin in patients with celiac disease and non-celiac gluten sensitivity. UEG Week Virtual Symposium 2020, abstract OP174 (https://www.esanum.com/today/posts/probiotic-provides-a-potential-adjuvant-treatment-to-gluten-free-diet, 2/11/2020) and WO2019/129807 (IDS).
Although the claims at issue are not identical, they are not patentably distinct from each other because the claimed inventions are drawn to methods of treating those having celiac disease comprising administering a composition comprising B. longum CNCM I-2618 (NCC2705), which would those in need of inhibiting the digestion of gluten or production of toxigenic/immunogenic gluten peptides. The compositions are administered enterally, encompassing orally administered formulations according to instant claims 9-10. The inventions differ in that the composition of reference patent claim 1 includes a sugar; however, the composition and methods of instant claims include the open-ended language “comprising” and thus the composition or administration of a sugar with B. longum is not excluded from the instant claims.
The inventions also differ in that the instant claims require administering twice daily one in the morning and evening with a meal and wherein the administering of the composition reduces duodenal glutenasic activity in the individual with celiac disease by at least 40% and wherein administration of the composition increases serpin concentration in the individual with celiac disease by at least 40%, which is measured from the administration of the gluten challenge to 370 minutes after the administration of the gluten challenge” of claims 3, and 25, and “measured after the administration of the gluten challenge” of claim 24.
Study Details | NCT03775499 | Probiotic BL NCC 2705 and Gluten Sensitivity | ClinicalTrials.gov , Record History 12/13/2018 document and 1/7/2019 document in view of Otten B. ( Safety of Bifidobacterium longum NCC 2705 and production of its serpin in patients with celiac disease and non-celiac gluten sensitivity. UEG Week Virtual Symposium 2020, abstract OP174 (https://www.esanum.com/today/posts/probiotic-provides-a-potential-adjuvant-treatment-to-gluten-free-diet, 2/11/2020) and WO2019/129807 (IDS).
The clinical trials document 2018 teaches a trial method wherein individuals having celiac disease are administered Bifidobacterium longum NCC2705, “1 capsule of BL NCC 2705 or placebo will be given twice a day in the morning and in the evening with a meal over 2 periods of 4 days. On day four a single dose of gluten (3g) will be administered and duodenal fluid will be collected in the following hours through a naso-intestinal catheter. The viability of BL NCC 2705, the production of serpin and its effects on gluten digestion and intestinal enzymatic activity will be determined.
Concentration of bacterial Serpin RNA and/or proteins (ng/mL) in duodenal aspirates Measurements via RT-PRC and immuno-assay [Time Frame: 19 sampling over 6h50 hours at visit 2 (day 4) and visit 3 (from day 22 to day 36)]
Concentration of Probiotic BL NCC 2705 (ng/mL) in duodenal aspirates Measurements via PCR [Time Frame: 19 sampling over 6h50 hours at visit 2 (day 4) and visit 3 (from day 22 to day 36)]
Concentration of gluten derived peptides in duodenal aspirates Effect of BL NCC 2705 on gluten digestion based on the amount of gluten peptides detected in duodenal aspirates [Time Frame: 10 sampling over 3h30 at visit 2 (day 4) and visit 3 (from day 22 to day 36)]
Concentration of gluten derived peptides in urine Effect of BL NCC 2705 on gluten digestion based on the amount of gluten peptides detected in urine [Time Frame: 10 sampling over 3h30 at visit 2 (day 4) and visit 3 (from day 22 to day 36)]
Level of elastase (Units/ mL) activity in duodenal aspirates Measurements of proteolytic activity-based assay [Time Frame: 19 sampling over 6h50 hours at visit 2 (day 4) and visit 3 (from day 22 to day 36).”
The clinical trials document 2019 teaches a trial method wherein “individuals having celiac disease are administered 1 capsule of Bifidobacterium longum NCC2705 twice a day in the morning and in the evening with a meal over 2 periods of 4 days.
On day four a single dose of gluten (3g) will be administered and duodenal fluid will be collected in the following hours through a naso-intestinal catheter. The viability of BL NCC 2705, the production of serpin and its effects on gluten digestion and intestinal enzymatic activity will be determined.
Concentration of bacterial Serpin RNA and/or proteins (ng/mL) in duodenal aspirates
Measurements via RT-PRC and immuno-assay
[Time Frame: 19 sampling over 6h50 hours at visit 2 (day 4) and visit 3 (from day 22 to day 36)]
Concentration of Probiotic BL NCC 2705 (ng/mL) in duodenal aspirates
Measurements via PCR
[Time Frame: 19 sampling over 6h50 hours at visit 2 (day 4) and visit 3 (from day 22 to day 36)]
Concentration of gluten derived peptides in duodenal aspirates
Effect of BL NCC 2705 on gluten digestion based on the amount of gluten peptides detected in duodenal aspirates
[Time Frame: 10 sampling over 3h30 at visit 2 (day 4) and visit 3 (from day 22 to day 36)]
Concentration of gluten derived peptides in urine
Effect of BL NCC 2705 on gluten digestion based on the amount of gluten peptides detected in urine
[Time Frame: 10 sampling over 3h30 at visit 2 (day 4) and visit 3 (from day 22 to day 36)]
Level of elastase (Units/ mL) activity in duodenal aspirates
Measurements of proteolytic activity-based assay
[Time Frame: 19 sampling over 6h50 hours at visit 2 (day 4) and visit 3 (from day 22 to day 36)
Thus, the above references teach a method of administering to an individual having celiac disease a composition comprising an amount of Bifidobacterium longum NCC2705 twice a day in the morning and in the evening with a meal. Glutenasic duodenal activity and duodenal serpin protein concentrations are measured after at least 3 days, i.e. 4 days, after administration of the composition, and are sampled over a period of 6h50 hours at visit 2 (on day 4), therefore meeting applicants limitation of “measured from the administration of the gluten challenge to 370 minutes after the administration of the gluten challenge” of claims 3, and 25, and meeting “measured after the administration of the gluten challenge” of claim 24.
Regarding claims 9 and 10, the composition is in the form of a dietary supplement in capsule form.
The references do not teach the amount of reduction of glutenasic activity or the increase in serpin concentration and is silent as to the effective amount of B. longum.
Otten teaches that B. longum NCC2705 has been shown to ameliorate gluten immunopathology though the production of serpin in the mouse model of celiac disease. Otten teaches the administration of B. longum NCC2705 to celiac patients and find that after intake of the probiotics (on the test day), B. longum NCC2705 was detected in the duodenal aspirates and serpin concentrations increased by 36%. Thus, the probiotic strain has use as an adjuvant treatment to gluten-free diet to protect from accidental gluten intake (p. 2, whole page).
WO’807 teaches a method comprising administering a composition comprising a therapeutically effective amount serpin protein producing B. longum strain CNCM I-2628 (NCC2705) to an individual in need thereof, wherein said individual has celiac disease and gluten-related/gluten-sensitivity disorders triggered by gluten (p. 1, lines 6-11, 21-p. 2, lines 1-6, p. 4, lines 29-31, p. 9, lines 26-p. 12, whole page). Celiac disease is triggered by the digestion of wheat gluten and other cereal proteins from rye and barley, for example (p. 1, lines 24-25). B. longum CNCM I-2618 is disclosed to be used in the treatment or prevention of conditions related to gluten sensitivity or involving reduced activity of serine protease inhibitors (p. 9, lines 26-28) including specifically celiac disease (p. 10, lines 2, 6, 7). Serine protease inhibitors are known to play a role in gluten-related disorders as having potent inhibitory capacity of elastases and proteinases and having a role in celiac disease by inhibiting transglutaminase 2, thus inhibiting deamidation of a 33-mer gliadin peptide (this activity is in itself glutenasic activity), which is a trigger of the adaptive immune response in celiac disease. The serpin protein of B. longum NCC2705 display similar antiprotease activity (p. 2, lines 10-30).
WO’807 teaches that “Clinical evidence shows class Il human leukocyte antigens (HLA-DQII), which strongly relate with celiac disease pathology, are expressed in about 95% of celiac disease patients. In the intestinal lumen, gluten proteins are partially digested, forming proteolytic-resistant 33-mer gluten peptides. After crossing the small intestinal barrier, they are deamidated by transglutaminase 2 (TG2) with negative charges (Sollid, 2000, Annual review of immunology, 18(1), 53-81), which then bind to the positively charged binding sites of HLA-DQ2.5/8 (Dieterich et al., 1997, Nature medicine, 3(7), 797-801). HLA-DQ2.5/8 displaying those specific gluten peptides signals to helper T cells and other immune cells causing further damage in the small intestine. Antibodies against gluten proteins and autoantibodies to connective tissue components (TG2) also associated with celiac disease progression (Alaedini & Green, 2005, Annals of internal medicine, 142(4), 289-298)” (p. 10, lines 19-28).
WO’807 teaches testing NCC2705 in animal models which were sensitized and then challenged with gluten (same as described in McCarville 2017). The strain is administered during the challenge at a dose of 1x109 CFU per day and intestinal content is collected to measure glutenasic activity (elastase activity, p. 15-16, Ex. 2). They find that the strain inhibits glutenasic activity and increases serpin concentration (see Fig. 1 and 2). According to Fig, 2, the elastase activity is reduced by at least 40% when administering the frozen and spray dried NCC2705 compared to control.
Regarding claim 4, WO’807 teaches that gluten contains the cytotoxic protein gliadin as well as other proteins/peptides which contribute to symptoms of gluten-related disorders including celiac disease. Serine protease inhibitors (serpins) have been shown to have potent inhibitory role in gluten-related disorders including potent antiprotease activity and B. longum subsp longum NCC2705 contains serpins having antiprotease activity and protect against proteases in the GI tract, which improve gluten induced pathophysiology in the mouse model of gluten sensitivity and thus is a solution for gluten related disorders (p. 2, lines 2-21, 27-31, p. 3, lines 1-6, Ex. 2 p. 15-16).
Regarding claims 9 and 10, WO’807 teach the composition comprising B. longum strain CNCM I-2628 (NCC2705) to be in the form of a food, medical food, nutritional supplement or pharmaceutical composition, a powder, a tablet, a capsule, and a lozenge (p. 4, lines 8-31, p. 5, lines 21-30, p. 7, lines 9-10).
Regarding claim 11, the composition comprises between 106-1010 cfu of B. longum NCC2705 per dose (p. 7, lines 20-23). Further, the reference teaches that the ideal dose will depend on the subject to be treated, which will vary but can be easily determined by those of skill in the art.
The claimed invention is drawn to a single step of administering a composition comprising therapeutically effective amount of a serpin producing B. longum strain CNCM I-2628 (NCC2705) to an individual in need, wherein said individual in need thereof has celiac disease.
WO’807 teaches the single method step of administering a composition comprising therapeutically effective amount of a serpin producing B. longum strain CNCM I-2628 (NCC2705) to an individual in need (those having gluten-related disorders), wherein said individual in need thereof has celiac disease. The reference teaches that serine protease inhibitors (serpins) have been shown to have potent inhibitory role in gluten-related disorders including potent antiprotease activity and B. longum subsp longum NCC2705 contains serpins having antiprotease activity and protect against proteases in the GI tract, which improve gluten induced pathophysiology and thus is a solution for gluten related disorders (p. 2, lines 2-21, 27-31, p. 3, lines 1-6, Ex. 2 p. 15-16). It is important to note that applicants state that the presence of serpin in the duodenum may confer advantageous properties such as reduced digestion of gluten by reduction of gluten-related proteolytic activity (0133, 0135).
While the cited reference does not teach that their composition is used in a method of inhibiting digestion of gluten, the intended use of the claimed composition does not patentably distinguish the composition, per se, since such undisclosed use is inherent in the reference composition. In order to be limiting, the intended use must create a structural difference between the claimed composition and the composition of the prior art. In the instant case, the intended use fails to create a structural difference, thus, the intended use is not limiting. Please note that when applicant claims a composition in terms of function, and the composition of the prior art appears to be the same, the Examiner may make rejections under both 35 U.S.C 102 and 103 (MPEP 2112). Moreover, the claimed function must be inherent to the reference composition. The discovery of a previously unappreciated property of a prior art composition, or of a scientific explanation for the prior art’s functioning, does not render the old composition patentably new. Thus, the claiming of a new use, functions or unknown property which is inherently present in the prior art does not necessarily make the claim patentable. (MPEP 2112)
II. INHERENT FEATURE NEED NOT BE RECOGNIZED AT THE TIME OF THE INVENTION
There is no requirement that a person of ordinary skill in the art would have recognized the inherent disclosure at the time of invention, but only that the subject matter is in fact inherent in the prior art reference. Schering Corp. v. Geneva Pharm. Inc., 339 F.3d 1373, 1377, 67 USPQ2d 1664, 1668 (Fed. Cir. 2003) (rejecting the contention that inherent anticipation requires recognition by a person of ordinary skill in the art before the critical date and allowing expert testimony with respect to post-critical date clinical trials to show inherency); see also Toro Co. v. Deere & Co., 355 F.3d 1313, 1320, 69 USPQ2d 1584, 1590 (Fed. Cir. 2004) ("[T]he fact that a characteristic is a necessary feature or result of a prior-art embodiment (that is itself sufficiently described and enabled) is enough for inherent anticipation, even if that fact was unknown at the time of the prior invention."); Abbott Labs v. Geneva Pharms., Inc., 182 F.3d 1315, 1319, 51 USPQ2d 1307, 1310 (Fed.Cir.1999) ("If a product that is offered for sale inherently possesses each of the limitations of the claims, then the invention is on sale, whether or not the parties to the transaction recognize that the product possesses the claimed characteristics."); Atlas Powder Co. v. IRECO, Inc., 190 F.3d 1342, 1348-49, 51 USPQ2d 1943, 1947 (Fed. Cir. 1999) ("Because ‘sufficient aeration’ was inherent in the prior art, it is irrelevant that the prior art did not recognize the key aspect of [the] invention.... An inherent structure, composition, or function is not necessarily known."); SmithKline Beecham Corp. v. Apotex Corp., 403 F.3d 1331, 1343-44, 74 USPQ2d 1398, 1406-07 (Fed. Cir. 2005) (holding that a prior art patent to an anhydrous form of a compound "inherently" anticipated the claimed hemihydrate form of the compound because practicing the process in the prior art to manufacture the anhydrous compound "inherently results in at least trace amounts of" the claimed hemihydrate even if the prior art did not discuss or recognize the hemihydrate); In re Omeprazole Patent Litigation, 483 F.3d 1364, 1373, 82 USPQ2d 1643, 1650 (Fed. Cir. 2007) (The court noted that although the inventors may not have recognized that a characteristic of the ingredients in the prior art method resulted in an in situ formation of a separating layer, the in situ formation was nevertheless inherent. "The record shows formation of the in situ separating layer in the prior art even though that process was not recognized at the time. The new realization alone does not render that necessary [sic] prior art patentable.").
Further, applicants’ amendments drawn to “wherein the administering of the composition reduces duodenal glutenasic activity in the individual with celiac disease by at least 40%” and “wherein administration of the composition increases serpin concentration in the individual with celiac disease by at least 40%” are taken to necessarily be happening when administering the same composition (in the claimed therapeutically effective amount demonstrated by WO807) to the same patient population, i.e. a result on the process step of administering. The whereby clause in a method claim is not given weight when it simply expresses the intended result of a process step positively recited.’" Id. (quoting Minton v. Nat’l Ass’n of Securities Dealers, Inc., 336 F.3d 1373, 1381, 67 USPQ2d. 1614, 1620 (Fed. Cir. 2003)). The only method step is administering, and thus the reduction of activity and increase in serpin concentration are only intended results of administering the composition, as well as a function of the preparation. The method of WO’807 is drawn to the same method as claimed, i.e. a B. longum CNCM I-2628 (NCC2705) composition administered to the same celiac subjects. Thus, it is the Examiners position that these results are inherent to the administration step taught by WO’807. One would necessarily expect to achieve the same results when practicing the method of WO’807, which is the same as applicants claimed method.
MPEP 2112 Requirements of Rejection Based on Inherency; Burden of Proof [R-08.2012]
The express, implicit, and inherent disclosures of a prior art reference may be relied upon in the rejection of claims under 35 U.S.C. 102 and 103. “The inherent teaching of a prior art reference, a question of fact, arises both in the context of anticipation and obviousness.” In re Napier, 55 F.3d 610, 613, 34 USPQ2d 1782, 1784 (Fed. Cir. 1995) (affirmed a 35 U.5.C. 103 rejection based in part on inherent disclosure in one of the references). See also In re Grasselli, 713 F.2d 731, 739, 218 USPQ 769, 775 (Fed. Cir. 1983).
Thus, before the effective filing date of the claimed invention, a phosita would have a reasonable expectation of successfully reducing glutenasic activity and increasing serpin concentration in an individual having celiac disease when administering NCC 2705 as taught by the clinical trials references, Otten, and in therapeutically effective amounts taught by WO’807 in light of the teachings of these prior art references. Further, the references teach measuring the activity and concentrations after a gluten challenge and thus methods to determine the efficacy of serpin producing bacteria to reduce glutenasic activity and measure concentrations of serpin in duodenal aspirates were known and practiced by the prior art references of record, and thus would have been obvious to a phosita before the effective filing of the claimed invention.
Therefore, the examined claims would be obvious over the reference patent claims.
Claims 3, 4, 9-11, 24, 25 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 14 and 15 of copending Application No. 17597304 (reference application) in view of Study Details | NCT03775499 | Probiotic BL NCC 2705 and Gluten Sensitivity | ClinicalTrials.gov , Record History 12/13/2018 document and 1/7/2019 document in view of Otten B. ( Safety of Bifidobacterium longum NCC 2705 and production of its serpin in patients with celiac disease and non-celiac gluten sensitivity. UEG Week Virtual Symposium 2020, abstract OP174 (https://www.esanum.com/today/posts/probiotic-provides-a-potential-adjuvant-treatment-to-gluten-free-diet, 2/11/2020) and WO2019/129807 (IDS).
Although the claims at issue are not identical, they are not patentably distinct from each other because the claimed inventions are drawn to methods of treating those having celiac disease comprising administering a composition comprising B. longum CNCM I-2618 (NCC2705), which would those in need of inhibiting the digestion of gluten or production of toxigenic/immunogenic gluten peptides. The inventions differ in that the composition of reference claim 14 includes a sugar; however, the composition and methods of instant claims include the open-ended language “comprising” and thus the composition or administration of a sugar with B. longum is not excluded from the instant claims. The inventions also differ in that the instant claims require administering twice daily one in the morning and evening with a meal and wherein the administering of the composition reduces duodenal glutenasic activity in the individual with celiac disease by at least 40% and wherein administration of the composition increases serpin concentration in the individual with celiac disease by at least 40%, which is measured from the administration of the gluten challenge to 370 minutes after the administration of the gluten challenge” of claims 3, and 25, and “measured after the administration of the gluten challenge” of claim 24.
Study Details | NCT03775499 | Probiotic BL NCC 2705 and Gluten Sensitivity | ClinicalTrials.gov , Record History 12/13/2018 document and 1/7/2019 document in view of Otten B. ( Safety of Bifidobacterium longum NCC 2705 and production of its serpin in patients with celiac disease and non-celiac gluten sensitivity. UEG Week Virtual Symposium 2020, abstract OP174 (https://www.esanum.com/today/posts/probiotic-provides-a-potential-adjuvant-treatment-to-gluten-free-diet, 2/11/2020) and WO2019/129807 (IDS).
The clinical trials document 2018 teaches a trial method wherein individuals having celiac disease are administered Bifidobacterium longum NCC2705, “1 capsule of BL NCC 2705 or placebo will be given twice a day in the morning and in the evening with a meal over 2 periods of 4 days. On day four a single dose of gluten (3g) will be administered and duodenal fluid will be collected in the following hours through a naso-intestinal catheter. The viability of BL NCC 2705, the production of serpin and its effects on gluten digestion and intestinal enzymatic activity will be determined.
Concentration of bacterial Serpin RNA and/or proteins (ng/mL) in duodenal aspirates Measurements via RT-PRC and immuno-assay [Time Frame: 19 sampling over 6h50 hours at visit 2 (day 4) and visit 3 (from day 22 to day 36)]
Concentration of Probiotic BL NCC 2705 (ng/mL) in duodenal aspirates Measurements via PCR [Time Frame: 19 sampling over 6h50 hours at visit 2 (day 4) and visit 3 (from day 22 to day 36)]
Concentration of gluten derived peptides in duodenal aspirates Effect of BL NCC 2705 on gluten digestion based on the amount of gluten peptides detected in duodenal aspirates [Time Frame: 10 sampling over 3h30 at visit 2 (day 4) and visit 3 (from day 22 to day 36)]
Concentration of gluten derived peptides in urine Effect of BL NCC 2705 on gluten digestion based on the amount of gluten peptides detected in urine [Time Frame: 10 sampling over 3h30 at visit 2 (day 4) and visit 3 (from day 22 to day 36)]
Level of elastase (Units/ mL) activity in duodenal aspirates Measurements of proteolytic activity-based assay [Time Frame: 19 sampling over 6h50 hours at visit 2 (day 4) and visit 3 (from day 22 to day 36).”
The clinical trials document 2019 teaches a trial method wherein “individuals having celiac disease are administered 1 capsule of Bifidobacterium longum NCC2705 twice a day in the morning and in the evening with a meal over 2 periods of 4 days.
On day four a single dose of gluten (3g) will be administered and duodenal fluid will be collected in the following hours through a naso-intestinal catheter. The viability of BL NCC 2705, the production of serpin and its effects on gluten digestion and intestinal enzymatic activity will be determined.
Concentration of bacterial Serpin RNA and/or proteins (ng/mL) in duodenal aspirates
Measurements via RT-PRC and immuno-assay
[Time Frame: 19 sampling over 6h50 hours at visit 2 (day 4) and visit 3 (from day 22 to day 36)]
Concentration of Probiotic BL NCC 2705 (ng/mL) in duodenal aspirates
Measurements via PCR
[Time Frame: 19 sampling over 6h50 hours at visit 2 (day 4) and visit 3 (from day 22 to day 36)]
Concentration of gluten derived peptides in duodenal aspirates
Effect of BL NCC 2705 on gluten digestion based on the amount of gluten peptides detected in duodenal aspirates
[Time Frame: 10 sampling over 3h30 at visit 2 (day 4) and visit 3 (from day 22 to day 36)]
Concentration of gluten derived peptides in urine
Effect of BL NCC 2705 on gluten digestion based on the amount of gluten peptides detected in urine
[Time Frame: 10 sampling over 3h30 at visit 2 (day 4) and visit 3 (from day 22 to day 36)]
Level of elastase (Units/ mL) activity in duodenal aspirates
Measurements of proteolytic activity-based assay
[Time Frame: 19 sampling over 6h50 hours at visit 2 (day 4) and visit 3 (from day 22 to day 36)
Thus, the above references teach a method of administering to an individual having celiac disease a composition comprising an amount of Bifidobacterium longum NCC2705 twice a day in the morning and in the evening with a meal. Glutenasic duodenal activity and duodenal serpin protein concentrations are measured after at least 3 days, i.e. 4 days, after administration of the composition, and are sampled over a period of 6h50 hours at visit 2 (on day 4), therefore meeting applicants limitation of “measured from the administration of the gluten challenge to 370 minutes after the administration of the gluten challenge” of claims 3, and 25, and meeting “measured after the administration of the gluten challenge” of claim 24.
Regarding claims 9 and 10, the composition is in the form of a dietary supplement in capsule form.
The references do not teach the amount of reduction of glutenasic activity or the increase in serpin concentration and is silent as to the effective amount of B. longum.
Otten teaches that B. longum NCC2705 has been shown to ameliorate gluten immunopathology though the production of serpin in the mouse model of celiac disease. Otten teaches the administration of B. longum NCC2705 to celiac patients and find that after intake of the probiotics (on the test day), B. longum NCC2705 was detected in the duodenal aspirates and serpin concentrations increased by 36%. Thus, the probiotic strain has use as an adjuvant treatment to gluten-free diet to protect from accidental gluten intake (p. 2, whole page).
WO’807 teaches a method comprising administering a composition comprising a therapeutically effective amount serpin protein producing B. longum strain CNCM I-2628 (NCC2705) to an individual in need thereof, wherein said individual has celiac disease and gluten-related/gluten-sensitivity disorders triggered by gluten (p. 1, lines 6-11, 21-p. 2, lines 1-6, p. 4, lines 29-31, p. 9, lines 26-p. 12, whole page). Celiac disease is triggered by the digestion of wheat gluten and other cereal proteins from rye and barley, for example (p. 1, lines 24-25). B. longum CNCM I-2618 is disclosed to be used in the treatment or prevention of conditions related to gluten sensitivity or involving reduced activity of serine protease inhibitors (p. 9, lines 26-28) including specifically celiac disease (p. 10, lines 2, 6, 7). Serine protease inhibitors are known to play a role in gluten-related disorders as having potent inhibitory capacity of elastases and proteinases and having a role in celiac disease by inhibiting transglutaminase 2, thus inhibiting deamidation of a 33-mer gliadin peptide (this activity is in itself glutenasic activity), which is a trigger of the adaptive immune response in celiac disease. The serpin protein of B. longum NCC2705 display similar antiprotease activity (p. 2, lines 10-30).
WO’807 teaches that “Clinical evidence shows class Il human leukocyte antigens (HLA-DQII), which strongly relate with celiac disease pathology, are expressed in about 95% of celiac disease patients. In the intestinal lumen, gluten proteins are partially digested, forming proteolytic-resistant 33-mer gluten peptides. After crossing the small intestinal barrier, they are deamidated by transglutaminase 2 (TG2) with negative charges (Sollid, 2000, Annual review of immunology, 18(1), 53-81), which then bind to the positively charged binding sites of HLA-DQ2.5/8 (Dieterich et al., 1997, Nature medicine, 3(7), 797-801). HLA-DQ2.5/8 displaying those specific gluten peptides signals to helper T cells and other immune cells causing further damage in the small intestine. Antibodies against gluten proteins and autoantibodies to connective tissue components (TG2) also associated with celiac disease progression (Alaedini & Green, 2005, Annals of internal medicine, 142(4), 289-298)” (p. 10, lines 19-28).
WO’807 teaches testing NCC2705 in animal models which were sensitized and then challenged with gluten (same as described in McCarville 2017). The strain is administered during the challenge at a dose of 1x109 CFU per day and intestinal content is collected to measure glutenasic activity (elastase activity, p. 15-16, Ex. 2). They find that the strain inhibits glutenasic activity and increases serpin concentration (see Fig. 1 and 2). According to Fig, 2, the elastase activity is reduced by at least 40% when administering the frozen and spray dried NCC2705 compared to control.
Regarding claim 4, WO’807 teaches that gluten contains the cytotoxic protein gliadin as well as other proteins/peptides which contribute to symptoms of gluten-related disorders including celiac disease. Serine protease inhibitors (serpins) have been shown to have potent inhibitory role in gluten-related disorders including potent antiprotease activity and B. longum subsp longum NCC2705 contains serpins having antiprotease activity and protect against proteases in the GI tract, which improve gluten induced pathophysiology in the mouse model of gluten sensitivity and thus is a solution for gluten related disorders (p. 2, lines 2-21, 27-31, p. 3, lines 1-6, Ex. 2 p. 15-16).
Regarding claims 9 and 10, WO’807 teach the composition comprising B. longum strain CNCM I-2628 (NCC2705) to be in the form of a food, medical food, nutritional supplement or pharmaceutical composition, a powder, a tablet, a capsule, and a lozenge (p. 4, lines 8-31, p. 5, lines 21-30, p. 7, lines 9-10).
Regarding claim 11, the composition comprises between 106-1010 cfu of B. longum NCC2705 per dose (p. 7, lines 20-23). Further, the reference teaches that the ideal dose will depend on the subject to be treated, which will vary but can be easily determined by those of skill in the art.
The claimed invention is drawn to a single step of administering a composition comprising therapeutically effective amount of a serpin producing B. longum strain CNCM I-2628 (NCC2705) to an individual in need, wherein said individual in need thereof has celiac disease.
WO’807 teaches the single method step of administering a composition comprising therapeutically effective amount of a serpin producing B. longum strain CNCM I-2628 (NCC2705) to an individual in need (those having gluten-related disorders), wherein said individual in need thereof has celiac disease. The reference teaches that serine protease inhibitors (serpins) have been shown to have potent inhibitory role in gluten-related disorders including potent antiprotease activity and B. longum subsp longum NCC2705 contains serpins having antiprotease activity and protect against proteases in the GI tract, which improve gluten induced pathophysiology and thus is a solution for gluten related disorders (p. 2, lines 2-21, 27-31, p. 3, lines 1-6, Ex. 2 p. 15-16). It is important to note that applicants state that the presence of serpin in the duodenum may confer advantageous properties such as reduced digestion of gluten by reduction of gluten-related proteolytic activity (0133, 0135).
While the cited reference does not teach that their composition is used in a method of inhibiting digestion of gluten, the intended use of the claimed composition does not patentably distinguish the composition, per se, since such undisclosed use is inherent in the reference composition. In order to be limiting, the intended use must create a structural difference between the claimed composition and the composition of the prior art. In the instant case, the intended use fails to create a structural difference, thus, the intended use is not limiting. Please note that when applicant claims a composition in terms of function, and the composition of the prior art appears to be the same, the Examiner may make rejections under both 35 U.S.C 102 and 103 (MPEP 2112). Moreover, the claimed function must be inherent to the reference composition. The discovery of a previously unappreciated property of a prior art composition, or of a scientific explanation for the prior art’s functioning, does not render the old composition patentably new. Thus, the claiming of a new use, functions or unknown property which is inherently present in the prior art does not necessarily make the claim patentable. (MPEP 2112)
II. INHERENT FEATURE NEED NOT BE RECOGNIZED AT THE TIME OF THE INVENTION
There is no requirement that a person of ordinary skill in the art would have recognized the inherent disclosure at the time of invention, but only that the subject matter is in fact inherent in the prior art reference. Schering Corp. v. Geneva Pharm. Inc., 339 F.3d 1373, 1377, 67 USPQ2d 1664, 1668 (Fed. Cir. 2003) (rejecting the contention that inherent anticipation requires recognition by a person of ordinary skill in the art before the critical date and allowing expert testimony with respect to post-critical date clinical trials to show inherency); see also Toro Co. v. Deere & Co., 355 F.3d 1313, 1320, 69 USPQ2d 1584, 1590 (Fed. Cir. 2004) ("[T]he fact that a characteristic is a necessary feature or result of a prior-art embodiment (that is itself sufficiently described and enabled) is enough for inherent anticipation, even if that fact was unknown at the time of the prior invention."); Abbott Labs v. Geneva Pharms., Inc., 182 F.3d 1315, 1319, 51 USPQ2d 1307, 1310 (Fed.Cir.1999) ("If a product that is offered for sale inherently possesses each of the limitations of the claims, then the invention is on sale, whether or not the parties to the transaction recognize that the product possesses the claimed characteristics."); Atlas Powder Co. v. IRECO, Inc., 190 F.3d 1342, 1348-49, 51 USPQ2d 1943, 1947 (Fed. Cir. 1999) ("Because ‘sufficient aeration’ was inherent in the prior art, it is irrelevant that the prior art did not recognize the key aspect of [the] invention.... An inherent structure, composition, or function is not necessarily known."); SmithKline Beecham Corp. v. Apotex Corp., 403 F.3d 1331, 1343-44, 74 USPQ2d 1398, 1406-07 (Fed. Cir. 2005) (holding that a prior art patent to an anhydrous form of a compound "inherently" anticipated the claimed hemihydrate form of the compound because practicing the process in the prior art to manufacture the anhydrous compound "inherently results in at least trace amounts of" the claimed hemihydrate even if the prior art did not discuss or recognize the hemihydrate); In re Omeprazole Patent Litigation, 483 F.3d 1364, 1373, 82 USPQ2d 1643, 1650 (Fed. Cir. 2007) (The court noted that although the inventors may not have recognized that a characteristic of the ingredients in the prior art method resulted in an in situ formation of a separating layer, the in situ formation was nevertheless inherent. "The record shows formation of the in situ separating layer in the prior art even though that process was not recognized at the time. The new realization alone does not render that necessary [sic] prior art patentable.").
Further, applicants’ amendments drawn to “wherein the administering of the composition reduces duodenal glutenasic activity in the individual with celiac disease by at least 40%” and “wherein administration of the composition increases serpin concentration in the individual with celiac disease by at least 40%” are taken to necessarily be happening when administering the same composition (in the claimed therapeutically effective amount demonstrated by WO807) to the same patient population, i.e. a result on the process step of administering. The whereby clause in a method claim is not given weight when it simply expresses the intended result of a process step positively recited.’" Id. (quoting Minton v. Nat’l Ass’n of Securities Dealers, Inc., 336 F.3d 1373, 1381, 67 USPQ2d. 1614, 1620 (Fed. Cir. 2003)). The only method step is administering, and thus the reduction of activity and increase in serpin concentration are only intended results of administering the composition, as well as a function of the preparation. The method of WO’807 is drawn to the same method as claimed, i.e. a B. longum CNCM I-2628 (NCC2705) composition administered to the same celiac subjects. Thus, it is the Examiners position that these results are inherent to the administration step taught by WO’807. One would necessarily expect to achieve the same results when practicing the method of WO’807, which is the same as applicants claimed method.
MPEP 2112 Requirements of Rejection Based on Inherency; Burden of Proof [R-08.2012]
The express, implicit, and inherent disclosures of a prior art reference may be relied upon in the rejection of claims under 35 U.S.C. 102 and 103. “The inherent teaching of a prior art reference, a question of fact, arises both in the context of anticipation and obviousness.” In re Napier, 55 F.3d 610, 613, 34 USPQ2d 1782, 1784 (Fed. Cir. 1995) (affirmed a 35 U.5.C. 103 rejection based in part on inherent disclosure in one of the references). See also In re Grasselli, 713 F.2d 731, 739, 218 USPQ 769, 775 (Fed. Cir. 1983).
Thus, before the effective filing date of the claimed invention, a phosita would have a reasonable expectation of successfully reducing glutenasic activity and increasing serpin concentration in an individual having celiac disease when administering NCC 2705 as taught by the clinical trials references, Otten, and in therapeutically effective amounts taught by WO’807 in light of the teachings of these prior art references. Further, the references teach measuring the activity and concentrations after a gluten challenge and thus methods to determine the efficacy of serpin producing bacteria to reduce glutenasic activity and measure concentrations of serpin in duodenal aspirates were known and practiced by the prior art references of record, and thus would have been obvious to a phosita before the effective filing of the claimed invention.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 3, 4, 9-11, 24, 25 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 4-7 of copending Application No. 19447621 (reference application) in view of Study Details | NCT03775499 | Probiotic BL NCC 2705 and Gluten Sensitivity | ClinicalTrials.gov , Record History 12/13/2018 document and 1/7/2019 document in view of Otten B. ( Safety of Bifidobacterium longum NCC 2705 and production of its serpin in patients with celiac disease and non-celiac gluten sensitivity. UEG Week Virtual Symposium 2020, abstract OP174 (https://www.esanum.com/today/posts/probiotic-provides-a-potential-adjuvant-treatment-to-gluten-free-diet, 2/11/2020) and WO2019/129807 (IDS).
Although the claims at issue are not identical, they are not patentably distinct from each other because the claimed inventions are drawn to methods of treating those having celiac disease comprising administering a composition comprising B. longum CNCM I-2618 (NCC2705), which would those in need of inhibiting the digestion of gluten or production of toxigenic/immunogenic gluten peptides. The inventions differ in that the composition of reference claim 4 includes a fructose disaccharide, FOS or combinations thereof; however, the composition and methods of instant claims include the open-ended language “comprising” and thus the composition or administration of a fructose disaccharide, FOS or combinations thereof with B. longum is not excluded from the instant claims. Therefore, the examined claims would be obvious over the reference claims.
The inventions also differ in that the instant claims require administering twice daily one in the morning and evening with a meal and wherein the administering of the composition reduces duodenal glutenasic activity in the individual with celiac disease by at least 40% and wherein administration of the composition increases serpin concentration in the individual with celiac disease by at least 40%, which is measured from the administration of the gluten challenge to 370 minutes after the administration of the gluten challenge” of claims 3, and 25, and “measured after the administration of the gluten challenge” of claim 24.
Study Details | NCT03775499 | Probiotic BL NCC 2705 and Gluten Sensitivity | ClinicalTrials.gov , Record History 12/13/2018 document and 1/7/2019 document in view of Otten B. ( Safety of Bifidobacterium longum NCC 2705 and production of its serpin in patients with celiac disease and non-celiac gluten sensitivity. UEG Week Virtual Symposium 2020, abstract OP174 (https://www.esanum.com/today/posts/probiotic-provides-a-potential-adjuvant-treatment-to-gluten-free-diet, 2/11/2020) and WO2019/129807 (IDS).
The clinical trials document 2018 teaches a trial method wherein individuals having celiac disease are administered Bifidobacterium longum NCC2705, “1 capsule of BL NCC 2705 or placebo will be given twice a day in the morning and in the evening with a meal over 2 periods of 4 days. On day four a single dose of gluten (3g) will be administered and duodenal fluid will be collected in the following hours through a naso-intestinal catheter. The viability of BL NCC 2705, the production of serpin and its effects on gluten digestion and intestinal enzymatic activity will be determined.
Concentration of bacterial Serpin RNA and/or proteins (ng/mL) in duodenal aspirates Measurements via RT-PRC and immuno-assay [Time Frame: 19 sampling over 6h50 hours at visit 2 (day 4) and visit 3 (from day 22 to day 36)]
Concentration of Probiotic BL NCC 2705 (ng/mL) in duodenal aspirates Measurements via PCR [Time Frame: 19 sampling over 6h50 hours at visit 2 (day 4) and visit 3 (from day 22 to day 36)]
Concentration of gluten derived peptides in duodenal aspirates Effect of BL NCC 2705 on gluten digestion based on the amount of gluten peptides detected in duodenal aspirates [Time Frame: 10 sampling over 3h30 at visit 2 (day 4) and visit 3 (from day 22 to day 36)]
Concentration of gluten derived peptides in urine Effect of BL NCC 2705 on gluten digestion based on the amount of gluten peptides detected in urine [Time Frame: 10 sampling over 3h30 at visit 2 (day 4) and visit 3 (from day 22 to day 36)]
Level of elastase (Units/ mL) activity in duodenal aspirates Measurements of proteolytic activity-based assay [Time Frame: 19 sampling over 6h50 hours at visit 2 (day 4) and visit 3 (from day 22 to day 36).”
The clinical trials document 2019 teaches a trial method wherein “individuals having celiac disease are administered 1 capsule of Bifidobacterium longum NCC2705 twice a day in the morning and in the evening with a meal over 2 periods of 4 days.
On day four a single dose of gluten (3g) will be administered and duodenal fluid will be collected in the following hours through a naso-intestinal catheter. The viability of BL NCC 2705, the production of serpin and its effects on gluten digestion and intestinal enzymatic activity will be determined.
Concentration of bacterial Serpin RNA and/or proteins (ng/mL) in duodenal aspirates
Measurements via RT-PRC and immuno-assay
[Time Frame: 19 sampling over 6h50 hours at visit 2 (day 4) and visit 3 (from day 22 to day 36)]
Concentration of Probiotic BL NCC 2705 (ng/mL) in duodenal aspirates
Measurements via PCR
[Time Frame: 19 sampling over 6h50 hours at visit 2 (day 4) and visit 3 (from day 22 to day 36)]
Concentration of gluten derived peptides in duodenal aspirates
Effect of BL NCC 2705 on gluten digestion based on the amount of gluten peptides detected in duodenal aspirates
[Time Frame: 10 sampling over 3h30 at visit 2 (day 4) and visit 3 (from day 22 to day 36)]
Concentration of gluten derived peptides in urine
Effect of BL NCC 2705 on gluten digestion based on the amount of gluten peptides detected in urine
[Time Frame: 10 sampling over 3h30 at visit 2 (day 4) and visit 3 (from day 22 to day 36)]
Level of elastase (Units/ mL) activity in duodenal aspirates
Measurements of proteolytic activity-based assay
[Time Frame: 19 sampling over 6h50 hours at visit 2 (day 4) and visit 3 (from day 22 to day 36)
Thus, the above references teach a method of administering to an individual having celiac disease a composition comprising an amount of Bifidobacterium longum NCC2705 twice a day in the morning and in the evening with a meal. Glutenasic duodenal activity and duodenal serpin protein concentrations are measured after at least 3 days, i.e. 4 days, after administration of the composition, and are sampled over a period of 6h50 hours at visit 2 (on day 4), therefore meeting applicants limitation of “measured from the administration of the gluten challenge to 370 minutes after the administration of the gluten challenge” of claims 3, and 25, and meeting “measured after the administration of the gluten challenge” of claim 24.
Regarding claims 9 and 10, the composition is in the form of a dietary supplement in capsule form.
The references do not teach the amount of reduction of glutenasic activity or the increase in serpin concentration and is silent as to the effective amount of B. longum.
Otten teaches that B. longum NCC2705 has been shown to ameliorate gluten immunopathology though the production of serpin in the mouse model of celiac disease. Otten teaches the administration of B. longum NCC2705 to celiac patients and find that after intake of the probiotics (on the test day), B. longum NCC2705 was detected in the duodenal aspirates and serpin concentrations increased by 36%. Thus, the probiotic strain has use as an adjuvant treatment to gluten-free diet to protect from accidental gluten intake (p. 2, whole page).
WO’807 teaches a method comprising administering a composition comprising a therapeutically effective amount serpin protein producing B. longum strain CNCM I-2628 (NCC2705) to an individual in need thereof, wherein said individual has celiac disease and gluten-related/gluten-sensitivity disorders triggered by gluten (p. 1, lines 6-11, 21-p. 2, lines 1-6, p. 4, lines 29-31, p. 9, lines 26-p. 12, whole page). Celiac disease is triggered by the digestion of wheat gluten and other cereal proteins from rye and barley, for example (p. 1, lines 24-25). B. longum CNCM I-2618 is disclosed to be used in the treatment or prevention of conditions related to gluten sensitivity or involving reduced activity of serine protease inhibitors (p. 9, lines 26-28) including specifically celiac disease (p. 10, lines 2, 6, 7). Serine protease inhibitors are known to play a role in gluten-related disorders as having potent inhibitory capacity of elastases and proteinases and having a role in celiac disease by inhibiting transglutaminase 2, thus inhibiting deamidation of a 33-mer gliadin peptide (this activity is in itself glutenasic activity), which is a trigger of the adaptive immune response in celiac disease. The serpin protein of B. longum NCC2705 display similar antiprotease activity (p. 2, lines 10-30).
WO’807 teaches that “Clinical evidence shows class Il human leukocyte antigens (HLA-DQII), which strongly relate with celiac disease pathology, are expressed in about 95% of celiac disease patients. In the intestinal lumen, gluten proteins are partially digested, forming proteolytic-resistant 33-mer gluten peptides. After crossing the small intestinal barrier, they are deamidated by transglutaminase 2 (TG2) with negative charges (Sollid, 2000, Annual review of immunology, 18(1), 53-81), which then bind to the positively charged binding sites of HLA-DQ2.5/8 (Dieterich et al., 1997, Nature medicine, 3(7), 797-801). HLA-DQ2.5/8 displaying those specific gluten peptides signals to helper T cells and other immune cells causing further damage in the small intestine. Antibodies against gluten proteins and autoantibodies to connective tissue components (TG2) also associated with celiac disease progression (Alaedini & Green, 2005, Annals of internal medicine, 142(4), 289-298)” (p. 10, lines 19-28).
WO’807 teaches testing NCC2705 in animal models which were sensitized and then challenged with gluten (same as described in McCarville 2017). The strain is administered during the challenge at a dose of 1x109 CFU per day and intestinal content is collected to measure glutenasic activity (elastase activity, p. 15-16, Ex. 2). They find that the strain inhibits glutenasic activity and increases serpin concentration (see Fig. 1 and 2). According to Fig, 2, the elastase activity is reduced by at least 40% when administering the frozen and spray dried NCC2705 compared to control.
Regarding claim 4, WO’807 teaches that gluten contains the cytotoxic protein gliadin as well as other proteins/peptides which contribute to symptoms of gluten-related disorders including celiac disease. Serine protease inhibitors (serpins) have been shown to have potent inhibitory role in gluten-related disorders including potent antiprotease activity and B. longum subsp longum NCC2705 contains serpins having antiprotease activity and protect against proteases in the GI tract, which improve gluten induced pathophysiology in the mouse model of gluten sensitivity and thus is a solution for gluten related disorders (p. 2, lines 2-21, 27-31, p. 3, lines 1-6, Ex. 2 p. 15-16).
Regarding claims 9 and 10, WO’807 teach the composition comprising B. longum strain CNCM I-2628 (NCC2705) to be in the form of a food, medical food, nutritional supplement or pharmaceutical composition, a powder, a tablet, a capsule, and a lozenge (p. 4, lines 8-31, p. 5, lines 21-30, p. 7, lines 9-10).
Regarding claim 11, the composition comprises between 106-1010 cfu of B. longum NCC2705 per dose (p. 7, lines 20-23). Further, the reference teaches that the ideal dose will depend on the subject to be treated, which will vary but can be easily determined by those of skill in the art.
The claimed invention is drawn to a single step of administering a composition comprising therapeutically effective amount of a serpin producing B. longum strain CNCM I-2628 (NCC2705) to an individual in need, wherein said individual in need thereof has celiac disease.
WO’807 teaches the single method step of administering a composition comprising therapeutically effective amount of a serpin producing B. longum strain CNCM I-2628 (NCC2705) to an individual in need (those having gluten-related disorders), wherein said individual in need thereof has celiac disease. The reference teaches that serine protease inhibitors (serpins) have been shown to have potent inhibitory role in gluten-related disorders including potent antiprotease activity and B. longum subsp longum NCC2705 contains serpins having antiprotease activity and protect against proteases in the GI tract, which improve gluten induced pathophysiology and thus is a solution for gluten related disorders (p. 2, lines 2-21, 27-31, p. 3, lines 1-6, Ex. 2 p. 15-16). It is important to note that applicants state that the presence of serpin in the duodenum may confer advantageous properties such as reduced digestion of gluten by reduction of gluten-related proteolytic activity (0133, 0135).
While the cited reference does not teach that their composition is used in a method of inhibiting digestion of gluten, the intended use of the claimed composition does not patentably distinguish the composition, per se, since such undisclosed use is inherent in the reference composition. In order to be limiting, the intended use must create a structural difference between the claimed composition and the composition of the prior art. In the instant case, the intended use fails to create a structural difference, thus, the intended use is not limiting. Please note that when applicant claims a composition in terms of function, and the composition of the prior art appears to be the same, the Examiner may make rejections under both 35 U.S.C 102 and 103 (MPEP 2112). Moreover, the claimed function must be inherent to the reference composition. The discovery of a previously unappreciated property of a prior art composition, or of a scientific explanation for the prior art’s functioning, does not render the old composition patentably new. Thus, the claiming of a new use, functions or unknown property which is inherently present in the prior art does not necessarily make the claim patentable. (MPEP 2112)
II. INHERENT FEATURE NEED NOT BE RECOGNIZED AT THE TIME OF THE INVENTION
There is no requirement that a person of ordinary skill in the art would have recognized the inherent disclosure at the time of invention, but only that the subject matter is in fact inherent in the prior art reference. Schering Corp. v. Geneva Pharm. Inc., 339 F.3d 1373, 1377, 67 USPQ2d 1664, 1668 (Fed. Cir. 2003) (rejecting the contention that inherent anticipation requires recognition by a person of ordinary skill in the art before the critical date and allowing expert testimony with respect to post-critical date clinical trials to show inherency); see also Toro Co. v. Deere & Co., 355 F.3d 1313, 1320, 69 USPQ2d 1584, 1590 (Fed. Cir. 2004) ("[T]he fact that a characteristic is a necessary feature or result of a prior-art embodiment (that is itself sufficiently described and enabled) is enough for inherent anticipation, even if that fact was unknown at the time of the prior invention."); Abbott Labs v. Geneva Pharms., Inc., 182 F.3d 1315, 1319, 51 USPQ2d 1307, 1310 (Fed.Cir.1999) ("If a product that is offered for sale inherently possesses each of the limitations of the claims, then the invention is on sale, whether or not the parties to the transaction recognize that the product possesses the claimed characteristics."); Atlas Powder Co. v. IRECO, Inc., 190 F.3d 1342, 1348-49, 51 USPQ2d 1943, 1947 (Fed. Cir. 1999) ("Because ‘sufficient aeration’ was inherent in the prior art, it is irrelevant that the prior art did not recognize the key aspect of [the] invention.... An inherent structure, composition, or function is not necessarily known."); SmithKline Beecham Corp. v. Apotex Corp., 403 F.3d 1331, 1343-44, 74 USPQ2d 1398, 1406-07 (Fed. Cir. 2005) (holding that a prior art patent to an anhydrous form of a compound "inherently" anticipated the claimed hemihydrate form of the compound because practicing the process in the prior art to manufacture the anhydrous compound "inherently results in at least trace amounts of" the claimed hemihydrate even if the prior art did not discuss or recognize the hemihydrate); In re Omeprazole Patent Litigation, 483 F.3d 1364, 1373, 82 USPQ2d 1643, 1650 (Fed. Cir. 2007) (The court noted that although the inventors may not have recognized that a characteristic of the ingredients in the prior art method resulted in an in situ formation of a separating layer, the in situ formation was nevertheless inherent. "The record shows formation of the in situ separating layer in the prior art even though that process was not recognized at the time. The new realization alone does not render that necessary [sic] prior art patentable.").
Further, applicants’ amendments drawn to “wherein the administering of the composition reduces duodenal glutenasic activity in the individual with celiac disease by at least 40%” and “wherein administration of the composition increases serpin concentration in the individual with celiac disease by at least 40%” are taken to necessarily be happening when administering the same composition (in the claimed therapeutically effective amount demonstrated by WO807) to the same patient population, i.e. a result on the process step of administering. The whereby clause in a method claim is not given weight when it simply expresses the intended result of a process step positively recited.’" Id. (quoting Minton v. Nat’l Ass’n of Securities Dealers, Inc., 336 F.3d 1373, 1381, 67 USPQ2d. 1614, 1620 (Fed. Cir. 2003)). The only method step is administering, and thus the reduction of activity and increase in serpin concentration are only intended results of administering the composition, as well as a function of the preparation. The method of WO’807 is drawn to the same method as claimed, i.e. a B. longum CNCM I-2628 (NCC2705) composition administered to the same celiac subjects. Thus, it is the Examiners position that these results are inherent to the administration step taught by WO’807. One would necessarily expect to achieve the same results when practicing the method of WO’807, which is the same as applicants claimed method.
MPEP 2112 Requirements of Rejection Based on Inherency; Burden of Proof [R-08.2012]
The express, implicit, and inherent disclosures of a prior art reference may be relied upon in the rejection of claims under 35 U.S.C. 102 and 103. “The inherent teaching of a prior art reference, a question of fact, arises both in the context of anticipation and obviousness.” In re Napier, 55 F.3d 610, 613, 34 USPQ2d 1782, 1784 (Fed. Cir. 1995) (affirmed a 35 U.5.C. 103 rejection based in part on inherent disclosure in one of the references). See also In re Grasselli, 713 F.2d 731, 739, 218 USPQ 769, 775 (Fed. Cir. 1983).
Thus, before the effective filing date of the claimed invention, a phosita would have a reasonable expectation of successfully reducing glutenasic activity and increasing serpin concentration in an individual having celiac disease when administering NCC 2705 as taught by the clinical trials references, Otten, and in therapeutically effective amounts taught by WO’807 in light of the teachings of these prior art references. Further, the references teach measuring the activity and concentrations after a gluten challenge and thus methods to determine the efficacy of serpin producing bacteria to reduce glutenasic activity and measure concentrations of serpin in duodenal aspirates were known and practiced by the prior art references of record, and thus would have been obvious to a phosita before the effective filing of the claimed invention.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to TIFFANY MAUREEN GOUGH whose telephone number is (571)272-0697. The examiner can normally be reached M-Thu 8-5.
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/TIFFANY M GOUGH/ Examiner, Art Unit 1651
/MELENIE L GORDON/Supervisory Patent Examiner, Art Unit 1651
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