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/EP2022/071125 filed on 07/27/2022. Acknowledgment is made of applicant's claim for foreign priority based on an application filed in ITALY on 07/28/2021. Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Response to Amendment
Applicant’s preliminary amendment filed on December 8, 2023 cancelling claims 1 and 5, amending claims 2-4 and 6-9, and adding new claim 10 has been entered. Claims 2-4 and 6-10 are currently pending and presented for examination.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 2-4 and 6-10 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
The term “related to” in claim 10 is a relative term which renders the claim indefinite. The term “related to” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. The specification does not define what is meant by related to the abnormal functioning of the thyroid hormone or how to determine if a particular condition is related to the abnormal functioning of the thyroid hormone. Related to can mean that there is some sort of connection but neither the claim nor the specification defines to what degree the connection needs to be in order to be considered related to the abnormal functioning of the thyroid hormone. Thus an ordinary skilled artisan could not ascertain the metes and bound of the claims. Therefore, claim 2 and all claims dependent upon claim 2 are rejected as being indefinite. For the sake of compact prosecution, the claims are being interpreted as a method for the treatment or prevention of the abnormal functioning of the thyroid hormone in a patient undergoing treatment with an orally administered proton pump inhibitor, comprising orally administering an ethanol-free glycerol solution of thyroid hormone T4 to a patient in need thereof.
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 2-4, 6-7 and 10 is/are rejected under 35 U.S.C. 103 as being unpatentable over Vita et al. (J Clin Endocrinol Metab 99: 4481– 4486, 2014 Provided on IDS) in view of Fossati et al. U.S. Publication No. 2018/0104204 A1.
Claims 2-4 and 6-10 of the instant application claim a method for the treatment or prevention of the abnormal functioning of the thyroid hormone in a patient undergoing treatment with an orally administered proton pump inhibitor, comprising orally administering an ethanol-free glycerol solution of thyroid hormone T4 to a patient in need thereof.
Vita et al. teaches that levothyroxine (LT4) is one of the most prescribed drugs worldwide for either replacement or suppressive purposes, wherein the classic formulation of LT4 is the tablet which contains a sodium salt of LT4 and a number of excipients (page 4482). Vita et al. teaches that an acid gastric pH is required to permit dissolution of LT4 and its arrival in the intestine, where LT4 is absorbed (page 4482). Vita et al. teaches that the dissolution of the LT4 tablet is impaired upon progressive increases in the ambient pH (page 4482). Vita et al. teaches that among the most prescribed drugs that interfere with the intestinal absorption of LT4 are the proton-pump inhibitors (PPIs), and the concomitant ingestion of LT4 and a PPI is relatively common (page 4482). Vita et al. teaches that therapy with PPIs neutralizes the TSH-suppressive effect of LT4, and thus to achieve a stable low level of TSH, the LT4 daily dose must be increased while taking a PPI (page 4482). Vita et al. teaches that new LT4 formulations, the soft gel capsule and the oral solution, have become available in some, but not all, countries, wherein the soft gel capsule contains LT4 dissolved in glycerin that is covered by a gelatin shell and this formulation is unaffected by changes in ambient pH (page 4482).
Vita et al. teaches that the aim of this study was to verify, in patients with PPI-induced tablet LT4 malabsorption (as proven by the failure of serum TSH to be normalized or suppressed), that switching from the tablet LT4 to the oral solution LT4 corrects the malabsorption problem (page 4482). Vita et al. teaches evaluating 24 patients, fourteen patients (58.3%) with primary hypothyroidism who take LT4 for replacement therapy, and 10 (41.7%) who take it for TSH suppression therapy (page 4482). All patients had impaired absorption of the LT4 tablet due to concomitant ingestion of PPIs (page 4482). The patients were taking the following PPIs for either gastroesophageal reflux disease or parietal cell antibody–negative gastritis: 9 patients taking omeprazole; 7 patients taking pantoprazole; 6 patients taking lansoprazole; and 2 patients taking esomeprazole (page 4482). Vita et al. teaches that while maintaining both the co-ingestion of LT4 at the same interval before the PPI and the LT4 daily dose, patients were switched from the tablet to the oral solution (pages 4482-4483). The liquid solution used was pre-dosed ampules of Tirosint soluzione orale (IBSA Italia s.r.l.) (page 4483). Vita et al. teaches that the LT4 daily dose in mg/kg for all patients treated was between 1.0 and 2.7 (Table 1 page 4483). Thus for an average size subject between 50 and 91 kg, the daily dosage for LT4 would be about 50 mg to about 250 mg.
Vita et al. teaches that these studies demonstrate that patients in whom tablet LT4 fails to normalize or suppress serum TSH because of the concomitant ingestion of PPI benefit from the switch from the tablet to the oral solution and that the absorption of LT4 is so much better that, in one sixth of patients, the daily dose has to be decreased (page 4485). This fact reflects better pharmacokinetics of the oral solution than of the tablet LT4 and the liquid formulation of LT4 has a greater area under the curve from 0 to 2 hours and a faster time to reach the maximal concentration in blood (~30 minutes) (page 4485).
Thus Vita et al. teaches a method for the treatment or prevention of the abnormal functioning of the thyroid hormone in a patient undergoing treatment with an orally administered proton pump inhibitor, comprising orally administering a solution of thyroid hormone T4 to a patient in need thereof.
Vita et al. does not teach that the T4 solution is an ethanol-free glycerol solution of T4. Vita et al. does not teach the specific amount of the dosage unit in 0.5 to 10 ml of solution as claimed.
Fossati et al. teaches highly stable alcohol-free, water-glycerol solutions of T4 thyroid hormone, with a reduced amount of T3 impurity, packaged via specific container arrangements (abstract). Fossati et al. teaches a pharmaceutical preparation of thyroid hormone T4 in an alcohol-free water-glycerol solution, suitable for oral administration and characterized by high physical, chemical and microbiological stability for use in the treatment of disorders caused by thyroid hormone deficiency [0002]. Fossati et al. teaches that T4 hormone is conveniently administered in the form of a solution, which allows a more precise dosing as compared to solid forms, however, the administration of T4 solutions presents some challenges including T4 solutions are reported to prematurely convert in part to T3 during storage [0010]. Due to the quite higher potency of T3 vs. T4, even a small amount of formed T3 may significantly increase the overall dosage of administered hormone, with potential consequences for the patient caused by over-dosing [0010]. Fossati et al. teaches that another difficulty derives from the low water solubility of thyroid hormones, causing them to partly precipitate from solutions during storage and/or in consequence of temperature changes [0011]. A partial improvement in this area occurs where the thyroid hormones are formulated in water-alcohol-glycerol solutions showing a good stability [0011]. However, a significant degree of instability was observed with regards to conversion of T4 into T3 [0011].
Fossati et al. teaches that it was unexpectedly found that the unwanted premature conversion of T4 to T3 in packaged solution can be significantly reduced if T4 is formulated in water-glycerol, alcohol-free solutions and thus the invention relates to highly stable alcohol-free water-glycerol solutions of T4 thyroid hormone, with a reduced amount of T3 impurity, which are packaged in ready-to-use container arrangements suitable to maintain a general stability of the solution [0012]-[0013].
Fossati et al. teaches a single-dose unit form containing about 5 to about 350 μg T4 thyroid hormone, or about 5 to about 250 μg T4 thyroid hormone in 1 g of water-glycerol solution ([0016] and [0034]). Fossati et al. specifically teaches preparing dosage forms comprising alcohol-free water-glycerol solution wherein the following amounts of T4 hormone were dissolved in 1.222 g of glycerol 85%: 25 μg, 50 μg, 75 μg, and 100 μg, obtaining the respective final concentrations of: 25 μg/mL, 50 μg/mL, 75 μg/mL, and 100 μg/mL [0049]. Fossati et al. specifically demonstrates that their alcohol-free formulations are more stable and contain less T4 to T3 conversion than alcohol containing formulations (Examples on pages 4-5).
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 Vita et al. which teaches a method for the treatment or prevention of the abnormal functioning of the thyroid hormone in a patient undergoing treatment with an orally administered proton pump inhibitor, comprising orally administering a solution of thyroid hormone T4, with the teachings of Vita et al. which specifically teach a pharmaceutical preparation of thyroid hormone T4 in an alcohol-free water-glycerol solution, suitable for oral administration and characterized by high physical, chemical and microbiological stability for use in the treatment of disorders caused by thyroid hormone deficiency. Thus since Fossati et al. specifically teaches that their alcohol-free water-glycerol formulations are more stable and has less T4 to T3 conversion than formulations containing alcohol, an ordinary skilled artisan would have been motivated to use the T4 formulation of Fossati et al. in the method of Vita et al. to arrive at the instant invention with a reasonable expectation of improved results.
With respect to the concentrations of the unit dosage forms as claimed in claims 2-4 of the instant application which recite 10-800 mg or 500-800 mg of T4 in 0.5 to 10 ml which is a concentration range of 1 mg/ml to 1.6 mg/ml or 50 mg/ml to 1.6 mg/ml, Fossati et al. teaches unit dosages forms having the following concentrations 25 μg/mL, 50 μg/mL, 75 μg/mL, and 100 μg/mL. Thus the amounts taught in Fossati et al. are within the range as claimed in the instant claims.
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) (The prior art taught carbon monoxide concentrations of "about 1-5%" while the claim was limited to "more than 5%." The court held that "about 1-5%" allowed for concentrations slightly above 5% thus the ranges overlapped.); In re Geisler, 116 F.3d 1465, 1469-71, 43 USPQ2d 1362, 1365-66 (Fed. Cir. 1997) (Claim reciting thickness of a protective layer as falling within a range of "50 to 100 Angstroms" considered prima facie obvious in view of prior art reference teaching that "for suitable protection, the thickness of the protective layer should be not less than about 10 nm [i.e., 100 Angstroms]." The court stated that "by stating that ‘suitable protection’ is provided if the protective layer is ‘about’ 100 Angstroms thick, [the prior art reference] directly teaches the use of a thickness within [applicant’s] claimed range.").
Thus the cited claims of the instant application are rendered obvious in view of the cited prior art teachings.
Claim 9 is rejected under 35 U.S.C. 103 as being unpatentable over Vita et al. (J Clin Endocrinol Metab 99: 4481– 4486, 2014 Provided on IDS) in view of Fossati et al. U.S. Publication No. 2018/0104204 A1 as applied to claims 2-4, 6-7 and 10 above and further in view of “Gastro-oesophageal reflux disease and dyspepsia in adults: investigation and management” Clinical guideline, Reference number:CG184, Published: 03 September 2014, Last updated: 18 October 2019 (herein referred to as CG184)
Claim 9 of the instant application further claims that the proton pump inhibitor is administered between 5 and 100 mg daily.
Vita et al. in view of Fossati et al. do not teach the daily dosage of the proton pump inhibitor administered.
However, Vita et al. teaches that the patients were taking the following PPIs for either gastroesophageal reflux disease or parietal cell antibody–negative gastritis: 9 patients taking omeprazole; 7 patients taking pantoprazole; 6 patients taking lansoprazole; and 2 patients taking esomeprazole (page 4482).
CG184 teaches interventions for the treatment of gastroesophageal reflux disease is found on Table 2 in appendix A (page 8) which is 40 mg once a day for esomeprazole, 30 mg once a day for lansoprazole, 40 mg once a day for omeprazole, and 40 mg once a day for pantoprazole (page 27).
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 treat the patients of Vita et al. taking the following PPIs for gastroesophageal reflux disease (GERD): 9 patients taking omeprazole; 7 patients taking pantoprazole; 6 patients taking lansoprazole; and 2 patients taking esomeprazole; according to the recommended dosages as taught by CG184 which is 40 mg once a day for esomeprazole, 30 mg once a day for lansoprazole, 40 mg once a day for omeprazole, and 40 mg once a day for pantoprazole. Thus, a person of ordinary skill in the art would have been motivated to treat the patients of Vita et al. having GERD with proton pump inhibitors according to dosages well-known in the art with a reasonable expectation of predictable results. Thus, the dosages as taught in the prior art fall within the claimed range of between 5 and 100 mg daily and therefore claim 9 of the instant application is rendered obvious in view of the cited prior art teachings.
Claim 8 is rejected under 35 U.S.C. 103 as being unpatentable over Vita et al. (J Clin Endocrinol Metab 99: 4481– 4486, 2014 Provided on IDS) in view of Fossati et al. U.S. Publication No. 2018/0104204 A1 as applied to claims 2-4, 6-7 and 10 above and further in view of Ronchi et al. (International Journal of Pharmaceutics, 567 (2019) 118416 pages 1-11).
Claims 8 of the instant application further claims that the proton pump inhibitor is administered in the form of a modified-release solution.
Vita et al. in view of Fossati et al. does not teach the proton pump inhibitor is administered in the form of a modified-release solution.
Ronchi et al. teaches that modified-release oral dosage forms are commonly used in pharmaceutics to delay or sustain the release of drugs, but they are only marketed as solid dosage forms such as capsules or tablets and therefore, the development of a liquid oral dosage form with modified-release properties has been keenly awaited to increase the compliance of patients with a swallowing impairment, such as pediatric, older or critically ill patients (abstract). Ronchi et al. teaches that a new technology has been developed that consists of multi-layered particles suspended extemporaneously in a syrup, using omeprazole as a model drug (abstract). This formulation utilizing polymers allowed stability and achieved the prevention of the early release of omeprazole when dispersed in the liquid carrier and when in the acidic environment of the stomach (abstract). It is able to protect omeprazole for 2 h in acidic medium at pH 1.2, while omeprazole was entirely released at pH 6.8 within 45 min (abstract). The oral delayed-release system based on a multi-layered particle technology, as described in Ronchi et al., has shown an innovative process that permitted reconstitutable omeprazole liquid dosage forms with modified-release properties to be obtained (page 11).
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 treat patients according to the teachings of Vita et al. being treated with PPIs in any form known in the art and also in need of T4 therapy. Since modified release PPI formulations were known in the art as taught by Ronchi et al., it would have been obvious to a person of ordinary skill in the art to treat the patients of Vita et al. with T4 and also in need of a PPI with a modified-release solution of a PPI known in the art with a reasonable expectation of similar results. Thus since modified-release solutions of PPIs are suitable forms of treatment as taught by Ronchi, a person of ordinary skill in the art would have been motivated to combine the modified-release solutions of PPI with the oral solution of T4 with the same expectation that the PPI would not interfere with T4 absorption.
Thus claim 8 of the instant application is rendered obvious in view of the cited prior art teachings.
Conclusion
Claims 1 and 5 are canceled. Claims 2-4 and 6-10 are rejected. No claims are allowed.
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/KARA R. MCMILLIAN/Primary Examiner, Art Unit 1623
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