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 .
Priority
This application is a national stage entry of PCT/IB2020/057316 Filed on August 3, 2020. Acknowledgment is made of applicant's claim for foreign priority based on an application filed in Italy on August 9, 2019. Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Response to Amendment
No amendments to the claims were made by Applicant’s reply filed December 16, 2025. Claims 2, 3, 9, 12-14 and 16 were previously canceled. Claims 1, 4-8, 10, 11, 15, 17 and 18 are currently pending and presented for examination.
Response to Arguments
Applicant's arguments filed December 16, 2025 have been fully considered but they are not persuasive.
Applicant argues that Tavakkoli is completely silent with regard to the administration of cholecalciferol as the active agent for the treatment of celiac disease as presently claimed and Kimball does not correct Tavakkoli's deficiencies, nor can it provide for the missing link because Kimball is completely silent with regard to a role of cholecalciferol to treat celiac disease. Applicant further argues that Tavakkoli describes that almost 60% of patients with celiac diseases evaluated were also vitamin D deficient and Kimball describes how to maintain a healthy level of Vitamin D in subjects belonging to the general public. However, Applicant argues that the combination of these references does not provide a motivation or a suggestion to a person of ordinary skill in the art to administer cholecalciferol to treat patients affected by celiac disease as presently claimed. Thus, Applicant argues that the combination of the cited references would not have rendered obvious the presently claimed invention to one skilled in the art. Applicant further argues that Agardh does not correct any deficiencies discussed above for Tavakkoli and Kimball, nor can it provide for the missing link. Applicant further argues that claim 11 should not be rejected for the same reasons as detailed above.
These arguments are found not persuasive since in response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). In the instant case, the rejection of record already states that Tavakkoli et al. does not teach the administration of vitamin D3 also known as cholecalciferol. However, Tavakkoli et al. specifically demonstrates that that almost 60% of patients with celiac disease were found to be vitamin D deficient or insufficient (page 517). Thus Tavakkoli et al. identifies a problem in patients with celiac disease which is reduced vitamin D levels. Furthermore, Kimball specifically teaches how to treat patients that are vitamin D deficient or insufficient with Vitamin D3 (cholecalciferol). Thus the teachings of Kimball provide a solution to the problem identified in Tavakkoli et al. Accordingly, the teachings of the prior art demonstrate that celiac disease leads to vitamin D deficiency or insufficiency and thus a person of ordinary skill in the art would have been motivated to administer Vitamin D3 (cholecalciferol) therapy to a patient with celiac disease with a reasonable expectation of treating celiac disease by treating vitamin D deficiency or insufficiency.
A reference is good not only for what it teaches by direct anticipation but also for what one of ordinary skill in the art might reasonably infer from the teachings. (In re Opprecht 12 USPQ 2d 1235, 1236 (Fed Cir. 1989); In re Bode 193 USPQ 12 (CCPA) 1976). "[I]n considering the disclosure of a reference, it is proper to take into account not only specific teachings of the reference but also the inferences which one skilled in the art would reasonably be expected to draw therefrom." In re Preda, 401 F.2d 825, 826, 159 USPQ 342, 344 (CCPA 1968); In re Lamberti, 545 F.2d 747, 750, 192 USPQ 278, 280 (CCPA 1976).
In the instant case, a skilled artisan would reasonably infer from the teachings of Tavakkoli et al. that patients with celiac disease would benefit from the administration of Vitamin D3 (cholecalciferol) since Tavakkoli et al. specifically demonstrates that almost 60% of patients with celiac disease were found to be vitamin D deficient or insufficient (page 517). Furthermore, Kimball specifically teaches administration of vitamin D3 in the amounts as claimed to treat vitamin D deficiency. Thus by following the teachings and suggestions of the prior art of record, a person of ordinary skill in the art would arrive at the instant invention of treating celiac disease by administering vitamin D3 (cholecalciferol).
Applicant’s remaining arguments with respect to the Agardh reference and with respect to claim 11 are found not persuasive for the same reasons as detailed above. Accordingly, the previous rejections under 35 USC 103 are hereby maintained and reproduced below. This action is FINAL.
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.
Claims 1, 4-8, 10, 17 and 18 are rejected under 35 U.S.C. 103 as being unpatentable over Tavakkoli et al. (J Clin Gastroenterol 2013;47:515–519) in view of Kimball et al. (Dermato-Endocrinology, April 13, 2017, Vol. 9, No. 1, e1300213.) The cited claims of the instant application claim a method for treating celiac disease in a subject in need thereof, said method consisting of administering a therapeutically effective amount of cholecalciferol as an active agent to said subject in need thereof, wherein cholecalciferol is in the form of a pharmaceutical composition or food supplement consisting essentially of cholecalciferol and at least one suitable excipient.
Claim 7 of the instant application claims administration of a dose of 0.4 mg/kg/day to 11 mg/kg/day which is equivalent to 1120 IU to 30,800 IU per day in a 70 kg person. Claim 17 of the instant application claims a dose of 0.8 mg/kg/day to 11 mg/kg/day which is equivalent to 2240 IU to 30,800 IU per day in a 70 kg person. Claim 18 of the instant application claims a dose of 4 mg/kg/day to 11 mg/kg/day which is equivalent to 11,200 IU to 30,800 IU per day in a 70 kg person or in a dose of 160 IU/kg/day to 430 IU/kg/day.
Tavakkoli et al. teaches that celiac disease (CD) is an autoimmune disorder induced by the ingestion of gluten in genetically predisposed individuals who carry the HLA-DQ2 or DQ-8 alleles, wherein CD commonly affects the gastrointestinal tract, classically causing diarrhea and malabsorption; in addition, it has multiple extraintestinal manifestations, including iron-deficiency anemia, osteoporosis, and dermatitis herpetiformis (page 515).
Tavakkoli et al. teaches that vitamin D deficiency or insufficiency (commonly defined as levels less than 20 and 20 to 30 mg/dL, respectively) has been estimated to affect up to 80% of the general US population and has been shown to be prevalent across all age groups, both sexes, and multiple geographic locations (page 515). Tavakkoli et al. teaches that common causes of vitamin D deficiency include reduced skin synthesis from skin pigmentation, increased catabolism from medications such as anticonvulsants and antiretroviral therapy, nutritional deficiencies, and malabsorptive disorders including celiac disease (page 515). Tavakkoli et al. teaches that a total of 530 patients were identified who had both celiac disease and a 25-hydroxyvitamin D level on record (Table 1 on page 516). Tavakkoli et al. teaches that among the 530 patients, 133 (25%) were vitamin D deficient and 180 (34%) were vitamin D insufficient (page 516). Tavakkoli et al. further teaches that the degree of villous atrophy was recorded in 191 patients, 36% of the cohort and of these 191 patients, 80 (42%) had Marsh 3C lesions, or total villous atrophy, whereas the remaining 111 patients had lesser degrees of villous atrophy (page 517). Among the 80 patients with total villous atrophy on diagnosis, 16 (20%) had a 25-hydroxyvitamin D level less than 20 mg/dL, as compared with 30 of the 111 (27%) patients with lesser degrees of villous atrophy (P = 0.34). Thus Tavakkoli et al. teaches that this study demonstrates that almost 60% of patients with celiac disease were found to be vitamin D deficient or insufficient (page 517).
Tavakkoli et al. does not teach the administration of vitamin D3 also known as cholecalciferol.
Kimball et al. teaches the amount of vitamin D3 supplementation required to achieve a serum 25(OH)D above 100 nmol/L is on average 5,000 IU/d and 2–3 times more for overweight and obese individuals (page 2). Kimball et al. teaches that Natural levels of 25(OH)D achieved through sun exposure in Maasai herdsman that is in the range of 100–150 nmol/l can also be achieved with oral intake of 5,000–10,000 IU/d (page 2). Kimball et al. teaches that the Endocrine Society Practice Guidelines recommend that up to 10,000 IUs daily was safe for adults (page 2). For an individual with a high body mass index (BMI), doses over 10,000 IU/d may be necessary to achieve a 25(OH)D of at least 100 nmol/L (page 2). Kimball et al. evaluated vitamin D supplementation at intakes up to 15,000 IU/d in a community setting on various parameters of calcium metabolism and potential toxicity (pages 2-3).
Kimball et al. demonstrates the effect of vitamin D supplementation at doses up to 15,000 IU/d in a community-based program on vitamin D status, calcium homeostasis as well as on kidney, liver and immune function (abstract). Kimball et al. teaches that participants were supplemented with a wide range of vitamin D doses (1,000-15,000 IU/d) aimed at achieving serum 25-hydroxyvitamin D [25(OH) D] levels of at least 100 nmol/L wherein serum 25(OH)D concentrations up to 300 nmol/L were achieved without perturbation of calcium homeostasis or incidence of toxicity and hypercalcemia and hypercalciuria were not related to an increase in 25(OH)D concentrations nor vitamin D dose (abstract). Kimball et al. teaches that to achieve serum 25(OH)D levels >100 nmol/L on average, required vitamin D intakes of 6,000 IU/d for normal Body Mass Index (BMI), 7,000 IU/d for overweight and 8,000 IU/d for obese and thus doses of vitamin D in excess of 6,000 IU/d were required to achieve serum 25(OH)D concentrations above 100 nmol/L, especially in individuals who were overweight or obese without any evidence of toxicity.
Kimball et al. teaches that the Endocrine Society concluded that ingestion of up to 10,000 IUs daily was not associated with any significant alteration in calcium metabolism and recommended that circulating levels of 25(OH)D to be at least 75 nmol/L with a preferred range of 100-150 nmol/L for maximum bone and muscle health (page 6). Kimball et al. teaches that the amount of vitamin D required to achieve serum 25(OH)D concentrations of at least 100 nmol/L, particularly in overweight and obese individuals was between 6,000-8,000 IU/d on average and some of the participants were taking as much as 15,000 IUs of vitamin D daily without any untoward toxicity (page 6). Kimball et al. teaches that the Endocrine Society recommended that a blood level of 25(OH)D up to 250 nmol/L was not associated with toxicity and that vitamin D toxicity is usually observed when the blood level is above 375 nmol/L and their data are consistent with this recommendation since some of the participants achieved serum 25(OH)D levels up to 300 nmol/L without any evidence of hypercalciuria or hypercalcemia and there was no significant reduction in the PTH levels in those participants who had the highest intakes of vitamin D and achieved blood levels of 25(OH)D above 250 nmol/L (page 6).
Kimball et al. further teaches that there was a subgroup of participants (n=285) that reported substantial intakes of vitamin D supplements (> 4,000 IU/d) that did not experience an increase in serum 25(OH)D concentrations (page 3). Kimball et al. teaches that conditions that could cause intestinal absorption [including Crohn’s disease, celiac disease, inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), ulcerative colitis, gastrointestinal esophageal reflux disease (GERD)] were present in 38% of these participants, which increased to 60% of the 285 participants when we included whether participants reported stomach issues (including bloating, stomach pain, indigestion, upset stomach) (page 3).
Accordingly, prior to the effective filing date of the claimed invention, it would have been obvious to a person of ordinary skill in the art to combine the teachings of Tavakkoli et al. which demonstrates that a majority of patients with celiac disease are vitamin D deficient or insufficient, with the teachings of Kimball et al. which teaches that the recommended circulating levels of 25(OH)D to be at least 75 nmol/L with a preferred range of 100-150 nmol/L for maximum bone and muscle health and that the amount of vitamin D3 required to achieve serum 25(OH)D concentrations of at least 100 nmol/L, particularly in overweight and obese individuals was between 6,000-8,000 IU/d on average and some needing as much as 15,000 IUs of vitamin D daily. Thus, a person of ordinary skill in the art would have been motivated to optimize the daily dosage of vitamin D3 for a subject that is vitamin D deficient or insufficient based on dosages well-known in the art as taught in Kimball et al, that is necessary in order to maintain the recommended levels for maximum bone and muscle health. Since Kimball et al. teaches that in patient with intestinal disorders such as celiac disease, substantial intakes of > 4,000 IU/d vitamin D supplementation did not result in an increase in serum 25(OH)D concentrations, an ordinary skilled artisan would have been motivated to administer higher amount of vitamin D3 since as 15,000 IUs of vitamin D daily was not show to have toxic effects. Thus Kimball et al. teaches and suggests administration of vitamin D3 within the claimed range in order to treat a patient with celiac disease and having vitamin D deficiency or insufficiency in order to achieve and maintain the recommended levels for maximum bone and muscle health.
In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990); In re Geisler, 116 F.3d 1465, 1469-71, 43 USPQ2d 1362, 1365-66 (Fed. Cir. 1997).
Therefore, since Tavakkoli et al. in view of Kimball et al. render obvious treating a subject with celiac disease with the same amount of cholecalciferol as claimed, the effects achieved by administering cholecalciferol to a subject with celiac disease as claimed in claims 4-6 are also rendered obvious. This is because administration of the same compound in the same amount to the same patient will necessarily have the same effects absent a showing to the contrary. "Products of identical chemical composition cannot have mutually exclusive properties." A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present. In re Spada, 911 F.2d 705,709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). Thus, administration of the same cholecalciferol compound in the same amount to the same subject will necessarily result in the reduction of intestinal villous atrophy, protection and regeneration of the intestinal epithelium as claimed.
Thus the cited claims of the instant application are rendered obvious in view of the cited prior art teachings.
Claim 15 is rejected under 35 U.S.C. 103 as being unpatentable over Tavakkoli et al. (J Clin Gastroenterol 2013;47:515–519) in view of Kimball et al. (Dermato-Endocrinology, April 13, 2017, Vol. 9, No. 1, e1300213) as applied to claims 1, 4-8, 10, 17 and 18 above and further in view of Agardh et al. WO 2018/130667 A1.
Claim 15 of the instant application claims further administering at least one probiotic.
Tavakkoli et al. in view of Kimball et al. is as set forth above.
Tavakkoli et al. in view of Kimball et al. does not teach further administering at least one probiotic.
Agardh et al. teaches that probiotics are useful for the treatment of celiac disease (see abstract).
Accordingly, prior to the effective filing date of the claimed invention, it would have been obvious to a person of ordinary skill in the art to combine the teachings of Tavakkoli et al. in view of Kimball et al. which render obvious treating a subject having celiac disease comprising the administration of cholecalciferol with the teachings of Agardh et al. with teaches that probiotics are also useful in the treatment of celiac disease. Thus a person of ordinary skill in the art would have been motivated to combine probiotics with the vitamin D3 supplement with a reasonable expectation of improved success in treating celiac disease.
"It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose ....[T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850,205 USPQ 1069, 1072 (CCPA 1980).
Thus claim 15 of the instant application is rendered obvious in view of the cited prior art teachings.
Claim 11 is rejected under 35 U.S.C. 103 as being unpatentable over Tavakkoli et al. (J Clin Gastroenterol 2013;47:515–519) in view of Kimball et al. (Dermato-Endocrinology, April 13, 2017, Vol. 9, No. 1, e1300213) as applied to claims 1, 4-8, 10, 17 and 18 above and further in view of Deltius (10,000 IU/ml oral drops solution of cholecalciferol (vitamin D3) Package leaflet, November 2014).
Claim 11 of the instant application claims the pharmaceutical composition or food supplement is in the form of a solution, suspension, gel emulsion or tincture and comprises cholecalciferol in a concentration of 10,000 IU/ml to 20,000 IU/ml.
Tavakkoli et al. in view of Kimball et al. is as set forth above.
Tavakkoli et al. in view of Kimball et al. does not teach the pharmaceutical composition or food supplement is in the form of a solution, suspension, gel emulsion or tincture and comprises cholecalciferol in a concentration of 10,000 IU/ml to 20,000 IU/ml.
Deltius teaches that prior to the effective filing date of the claimed invention, a suitable form of Cholecalciferol (vitamin D3) was available as a 10,000 I.U. /ml oral drops, solution (title). DELTIUS oral drops are used to prevent vitamin D3 deficiency in children and adults with problems in absorbing food (malabsorption) defined by doctor (page 1).
Accordingly, prior to the effective filing date of the claimed invention, it would have been obvious to a person of ordinary skill in the art to combine the teachings of Tavakkoli et al. in view of Kimball et al. which render obvious treating a subject having celiac disease comprising the administration of cholecalciferol with the teachings of Deltius which teaches that prior to the effective filing date of the claimed invention, a suitable form of Cholecalciferol (vitamin D3) was available as a 10,000 I.U. /ml oral drops, solution used to prevent and treat vitamin D3 deficiency in children and adults with problems in absorbing food (malabsorption) defined by doctor (page 1). Thus a person of ordinary skill in the art would have been motivated to administer the Cholecalciferol oral drops, solution as a suitable form with a reasonable expectation of similar results as compared to other oral dosage forms.
Thus claim 11 of the instant application is rendered obvious in view of the prior art teachings.
Conclusion
Claims 1, 4-8, 10, 11, 15, 17 and 18 are rejected. Claims 2, 3, 9, 12-14 and 16 are canceled. No claims are allowed.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/KARA R. MCMILLIAN/Primary Examiner, Art Unit 1623
KRM