DEAILED 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 .
Election/Restrictions
To summarize, the applicant elected Group I, with traverse in the reply filed on January 27, 2021.
The requirement is still deemed proper and is therefore made FINAL.
Claim Rejections - 35 USC § 103
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 6, 74-76, and 78 are rejected under 35 U.S.C. 103 as being unpatentable over McCleary (previously cited) in view of Scott (previously cited), Foley et al. (previously cited), Zerwekh et al. (previously cited), Jie et al. (previously cited), Tomiuga et al. (previously cited), Bolster et al. (previously cited), and Zhan (previously cited).
McCleary teaches the administration of an oral preparation to support calcium metabolism and proper kidney function (see abstract and paragraph 9). They teach that the compositions are also useful to treat abnormal calcium metabolic conditions such as hypercalciuria and calcium nephrolithiasis (see paragraphs 25 and 32, and 37; instant claims 1 and 6). The compositions are taught and exemplified to include vitamin K and are given to human patients (see paragraph 44 and example 3, and claims 15 and 18). Citrate salts such as magnesium citrate and potassium citrate are envisioned components (see paragraph 12). Example 3 highlights the composition in order to combat skeletal calcium loss via an oral administration to a human where a vitamin K, KHCO₃ (bicarbonate salt), NaHCO₃ (bicarbonate salt), and a vitamin B are included (see paragraphs 5-7 and example 3). Potassium is also present in the composition and exemplified at 195 mg per dose (see example 3). The compositions are taught to include a citrate ions as well as potassium and magnesium ions to reduce urinary calcium loss (see paragraphs 12 and 30; instant claim 1). Treatment of hypercalciuria with a combination of vitamin k2, potassium citrate, magnesium citrate, a bicarbonate salt, magnesium oxide, potassium citrate and vitamin B6 is not explicitly detailed.
Foley et al. further teaches that normal levels of urinary calcium span from 100 to 250 mg over the course of 24 hours and elevated levels (hypercalciuria) are deemed to occur above a value of 300 mg over 24 hours (see page 683 second column).
Vitamins K1 and K2 are highlighted by the prior art as effective treatments to lower urinary calcium in hypercalciuria patients. Jie et al. teach of the oral administration of vitamin K1 to human patients and the resulting impact on excess urinary calcium excretion (see abstract). Several patients had a urinary ratio of calcium to creatinine of greater than 0.15, which according to Foley et al. corresponds to hypercalciuria (see figure 1 and Foley et al. page 685 first column first full paragraph). Oral administration of vitamin K1 resulted in a reduction in the urinary ratio of calcium to creatinine (see page 101 first column fourth full paragraph and figure 1; instant claim 76). Tomiuga et al. teach rats having hypercalciuria that are treated with menatetrenone (vitamin K2, MK-4) to treat the excess of calcium excreted in their urine (see abstract and page 35). In addition, there are a finite number of varieties of vitamin K, namely K1, K2, K3, K4 and K5 (see Bolster et al. paragraph 28). The vitamins K1 and K2 include menaquinone (MK7), menatetrenone (MK4), phylloquinone, and phytomenadione.
Scott details the occurrence of two related pathologies in the same patients (see paragraph 13). To address this issue, they teach a combination oral therapy, where an active agent known to treat one of the conditions is included along with an active agent to treat the other condition (see paragraphs 1, 13, and 176-177). This combination is taught to facilitate patient compliance (see paragraph 13).
Zerwekh et al. teach that hypercalciuria commonly occurs in human patients with nephrolithiasis, where the latter is characterized by (kidney) stone formation (see page 869-871).
Zhan teaches the administration of a combination of vitamin B6, potassium citrate, and magnesium oxide to humans to prevent the formation of kidney stones due to the presence of calcium (see paragraph 1-2, 4, and 8, and 11; instant claims 5-6 and 77). The potassium citrate is present at 1-10 g (see paragraph 8). Various oral compliant dosage forms such as pills, tablets, and capsules are envisioned (see paragraph 8).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to treat human patients with calcium nephrolithiasis and hypercalciuria by orally administering a combination dosage form of McCleary and Zhan et al. Specifically, the components of the example 3 composition of McCleary with its vitamin K, KHCO₃ (bicarbonate salt), NaHCO₃ (bicarbonate salt), and a vitamin B, where vitamin K2 or a combination of vitamin K1 and vitamin K2 is included as the vitamin K along with a taught citrate salt, namely magnesium citrate and/or potassium citrate, would have been obvious to select for addressing the hypercalciuria (see instant claims 6 and 76). These choices of components would have been obvious based upon the guidance provided by McCleary regarding the citrate addition as well as that of Jie et al. and Tomiuga et al., who point to the effectiveness of the vitamin K varieties against hypercalciuria. In addition, there is a small and finite number of options for vitamin K that can be included and for this additional reason, the selection of any one of them would have been obvious (see instant claims 74-75). The diagnosis of the hypercalciuria based upon the recognized urinary calcium level as taught by Foley et al. would have been obvious as well so as to identify the relevant recipient patient population. In light of Zerwekh et al., Zhan, and Scott, it also would have been obvious to include vitamin B6, potassium citrate, and magnesium oxide, where the potassium amount is present based upon the teachings of potassium citrate amount by Zhan. This modification is obvious because 1) McCleary already envisioned treating both calcium nephrolithiasis and hypercalciuria, 2) Zerwekh et al. teach that both conditions were known to occur in the same patient, 3) the full combination of ingredients would address both conditions with a single formulation as Scott teaches is desirable, and 4) Zhan teaches their trio of ingredients for treating the nephrolithiasis. The modification is also obvious as the application of the same technique to a similar product in order to yield the same improvement (e.g., ability to treat calcium nephrolithiasis). The modification would additionally have been obvious because the components of Zhan reduce the formation of calcium containing stones as McCleary desires and includes ingredients taught to be useful by McCleary, such as magnesium citrate and potassium. The administered composition then includes bicarbonate salts, vitamin K1 and/or vitamin K2, magnesium citrate, vitamin B6, potassium citrate, and magnesium oxide. Therefore claims 6, 74-76, and 78 are obvious over McCleary in view of Jie et al., Tomiuga et al., Foley et al., Zerwekh et al., Scott, Bolster et al., and Zhan.
Response to Arguments
Applicant's arguments filed August 6, 2025 have been fully considered. In light of the amendment to the claims, the rejection under 35 USC 103 over Rudman et al. in view of Scott, Reddy et al., McCleary Jie et al., Tomiuga et al., and Bolster et al. as evidenced by Foley et al. is hereby withdrawn. The applicant’s arguments against the remaining rejection are unpersuasive.
The applicant argues that the combination of references does not suggest the claimed combination of ingredients. To the contrary, the rejection details the combination and administration of two sets of active ingredients to address a combination of conditions known to occur in the same human patients, one of which hypercalciuria. The two sets of ingredients include all the claimed components.
The applicant argues that the cited prior art did not teach selecting patients with a 24 hr urinary excretion of greater than 200 mg calcium in effort to treat hypercalciuria. This argument appears to overlook the discussion of Foley that noted the range for normal and elevated levels of 24 hr urinary excretion levels of calcium present in patients, where values greater than 300 mg correspond to the latter. The condition where elevated levels occur can be described as hypercalciuria. This categorization aligns with that of Jones et al. which deem the upper limit of normal calcium excretion, and therefore the start of hypercalciuria, occurring at 250 mg for 24 urinary excretion of calcium (see page 557 first column first full paragraph – previously cited).
The applicant also argues that the claimed combination produced an advantage for treating hypercalciuria. The data in the specification does not support this characterization because administration of the claimed combination was not necessary to yield a decrease of urinary calcium excretion of greater the 50%, according to the evidence of record. Case 1 in instant table 1 only administered one of the claimed ingredients, vitamin K2, and the result was a greater than 50% reduction in excreted urinary calcium. The applicant references this case and cases 2-3 in the same table as examples of the claimed combination being effective and the potassium citrate supplementation not being expected to be effective in this regard. These data show that administration or potassium citrate at the tested doses is insufficient to bring the test subjects to normal levels of calcium excretion, but do not speak to the expected impact of potassium citrate supplementation calcium excretion. Since the calcium excretion level before the administration of each claimed ingredient separately was not tested, there is no basis to conclude that other members of the claimed combination are critical to the effect seen due to vitamin K2 administration. The data in the specification does not show an unexpectedly superior result due to the claimed combination, as the applicant implies. Instead it indicates that the tested vitamin K2 compound is effective in reducing urinary excretion of calcium in the presence or absence of allopurinol and vitamin B6 as well as several magnesium, citrate, and/or potassium sources.
In contrast to the applicant’s argument, there is a reasonable expectation of success in humans for the instantly claimed treatment. Vitamin K1 was already known to be effective in lowering urinary excretion of calcium in humans, so at minimum, the embodiments discussed as obvious by the rejection that administer vitamin K1 had an expectation of success. Further, vitamin K1 and vitamin K2 are both vitamin K compounds that are structurally similar. They were already collectively known for their role in calcium metabolism (Gröber et al. page 1 second column-page 2 first partial paragraph and table 1 – previously cited). Thus the additional work in rats explicitly testing vitamin K2 for action against excessive calcium excretion, that was already known to occur for vitamin K1 in humans, is sufficient to support a reasonable expectation of success for the person of ordinary skill in this art.
Conclusion
No claim is allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CARALYNNE E HELM whose telephone number is (571)270-3506. The examiner can normally be reached Mon-Fri 9-5.
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/CARALYNNE E HELM/Examiner, Art Unit 1615
/MELISSA S MERCIER/Primary Examiner, Art Unit 1615