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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 11 June 2026 has been entered.
Claims 1, 4-8, 12-14, 24, and 25, submitted on 11 June 2026, represent all claims currently under consideration.
Information Disclosure Statement
One Information Disclosure Statement (IDS), submitted on 11 June 2026, is acknowledged and has been considered.
Specification
Applicant is reminded of the proper language and format for an abstract of the disclosure.
The abstract should be in narrative form and generally limited to a single paragraph on a separate sheet within the range of 50 to 150 words in length. The abstract should describe the disclosure sufficiently to assist readers in deciding whether there is a need for consulting the full patent text for details.
The language should be clear and concise and should not repeat information given in the title. It should avoid using phrases which can be implied, such as, “The disclosure concerns,” “The disclosure defined by this invention,” “The disclosure describes,” etc. In addition, the form and legal phraseology often used in patent claims, such as “means” and “said,” should be avoided.
The abstract of the disclosure is objected to because it is less than 50 words long. A corrected abstract of the disclosure is required and must be presented on a separate sheet, apart from any other text. See MPEP § 608.01(b).
Response to Arguments
The 35 U.S.C. § 103 rejection of Claims 1, 4-8, 12-14, 24, and 25 over Miller in view of Loftsson is withdrawn. Applicant argues that Miller does not disclose a once-daily administration of CM4620-IE, but rather, each patient received a median of 3 doses over the course of the multi-day study, indicating that each patient did not necessarily receive a dose every day, demonstrating that the dosing regimen of Miller differs from the claimed once-daily administration. Applicant further argues that nothing in Lofsson specifically points towards a once-daily administration as opposed to any other dosing regimen. Applicant also argues that general pharmacokinetic principles cannot be applied to predicting dosing in acute kidney injury patients. Applicant has provided Exhibit 1, demonstrating that critical ill patients develop increased volumes of distribution, necessitating higher doses of the drug to ensure desired clinical effect in severe acute pancreatitis, the disease state which CM4620-IE was used in. The cause of the increased volume of distribution is caused by the disease itself. Thus, the artisan would not be able to extrapolate the dosing applied by Miller to the treatment of acute kidney injury, where patients have their own dosing considerations due to the disease state. Applicant further argues that Miller’s study was done in patients with acute pancreatitis, and reported the development of acute kidney injury as a secondary outcome, with 1 patient (8.3%) in the CM4620-IE group and 1 patient (20%) in the placebo group developing AKI. These results do not establish that once-daily dosing specifically would be effective in treating AKI, with the dosing regimen of Miller being designed for acute pancreatitis, not AKI. The Examiner finds these arguments to be persuasive.
Claim Rejections - 35 USC § 103
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 1, 4-8, 12-14, 24, and 25 are rejected under 35 U.S.C. 103 as being unpatentable over Basile (WO 2020/072942; Publication Date: 9 April 2020) in view of Miller (Annals of Emergency Medicine, Vol. 74, No. 4, 1 October 2019) and Blanco (Healthcare, 2019, 7(1), 10).
Determining the Scope and Contents of the Prior Art:
Basile (See IDS, 9 March 2023) discloses to treat a renal disorder in a mammal in need thereof by administering to the mammal in need of treatment an effective amount of a store operated calcium entry (SOCE) inhibitor or a pharmaceutically acceptable salt thereof (Abstract). The invention further provides a pharmaceutical composition comprising one or more SOCE inhibitor with one or more pharmaceutically acceptable carrier, diluent or excipient (Page 5, Lines 3-5). This invention provides a method to inhibit the differentiation of a CD4+ cell to a T-helper 17 (TH17) cell, comprising administering to a mammal an effective amount of a SOCE inhibitor or a pharmaceutically acceptable salt thereof (Page 5, Lines 10-13). The invention further provides a method to decrease an amount of pro-inflammatory cytokine interleukin 17 (IL-17), the method comprising administering to a mammal an effective amount of a SOCE inhibitor or pharmaceutically acceptable salt thereof. The invention also provides a method to decrease an amount of Ca2+ release-activated Ca2+ channel pore forming subunit OraI1, the method comprising administering to a mammal an effective amount of a SOCE inhibitor (Page 5, Lines 14-25). The SOCE inhibitors of the invention are any compound that interferes with the mechanism by which release of calcium ions from intracellular stores is coordinated with ion influx across the plasma membrane (Page 5, Lines 29-31). Exemplary SOCE inhibitors include CM4620 (the compound claimed in examined Claim 1) (Page 6, Lines 4-6). Renal disorders include, but are not limited to, acute kidney injury (Page 7, Line 10). Table 2 (Page 13) demonstrates that use of SOCE inhibitors reduces prevalence of Th17 cells in acute kidney injury, demonstrating mechanism that this inhibition utilizes. IL-17 expression is almost exclusive to cells expressing Orai1 cells, with results suggesting that Orai1 mediated SOCE channel is required for Th17 differentiation following injury (Page 18, Lines 8-13). The plasma protein Orai (ORAI1 and ORAI2) forms the pore of the CRAC channel. The protein ORAI1 is a structural component of the CRAC calcium channel. ORAI1 interacts with the STIM1 protein.
Basile does not explicitly disclose that the CM4620 is formulated as a unit dosage form, or a once daily administration.
Miller (See IDS, 9 March 2023) discloses the intracellular calcium signaling inhibitor CM4620 (also known as auxora, the compound of examined Claim 1) in the form of an injectable emulsion (a unit dosage form) which reduces the development of acute kidney injury in patients with acute pancreatitis (Table 1). The drug is administered at 1.0 mg/kg on day 1 and 1.4 mg/kg on Days 2-4 in phase 1. In phase 2, females received the same dosages as in phase 1, while males received 2.08 mg/kg on days 1-2 and 1.6 mg/kg on days 3-4 of the injectable emulsion. The data of Miller (Table 1) and those of the specification of the examined application (Example 2, Paragraph 00186) show that within the sub-group that received the placebo, 20% of patients developed acute kidney injury, while in sub-group received the injectable emulsion of auxora had 8% of patients develop AKI.
Miller does not state that the injectable emulsion is administered once daily.
Blanco a review of the impact of acute kidney injury (AKI) on the pharmacokinetics of drugs and how this alters drug prescription. Impaired kidney function is associated with decreased activity of several hepatic and gastrointestinal drug-metabolizing enzymes and transporters, and as such, drug dosage adjustments based only on kidney alteration could be insufficient in AKI. There are significant pharmacokinetic changes in protein binding, serum amino acid levels, liver, kidney, and intestinal metabolism in AKI. Thus, the determination of plasma drug concentrations is a very useful tool for monitoring and dose adjustments in AKI patients (Abstract). The effectiveness of a drug depends on its therapeutic level in the site of action, phenomena that usually result from an adequate balance of its administered dose, frequency of prescription, body distribution, liver metabolism, and renal clearance. In critically ill patients, pharmacokinetic data is of the utmost importance to guide dosing, as these patients tend to have an increased volume of distribution, low albumin concentration and altered drug metabolism and clearances (Page 2). The volume of distribution for the free drug (active form) is quite different from the volume of distribution of the total drug, and the exact concentration of free drug is extremely sensitive to plasma protein concentration and uremic toxins in AKI. In this sense, there is usually an increase in free fraction of drugs in AKI patients, since on one hand there is usually hypoalbuminemia in this setting, and on the other hand, the uremic toxins can displace drugs from their protein binding. Blood flow distribution to splanchnic circulation, skeletal muscle, and fat is altered in AKI, therefore the apparent volume of distribution of drugs is also changed over the dosing cycle and illness course. The free fraction of many drugs is increased in AKI (2. Protein Binding and Distribution). Figure 1 (Page 3) shows pharmacokinetic changes in AKI, including a prolonged drug half-life due to reduced drug metabolism and reduced drug clearance, as well as increased drug free fraction. Except in the cases in which a particular dose-related side effect is a known concern, it may be preferred to err on the side of higher not lower doses (9. Dose Adjustment in AKI Patients- Recommendations).
Ascertaining the Differences Between the Prior Art and the Claims at Issue:
The prior art does not specifically teach a once daily administration of CM4620 for the treatment of acute kidney injury.
Resolving the Level of Ordinary Skill in the Pertinent Art:
The artisan would have a medical degree, as well as extensive training in nephrology. This training would include pharmacokinetics and management of diseases such as acute kidney injury using pharmaceuticals.
Considering Objective Evidence Present in the Application Indicating Obviousness or Nonobviousness:
Basile, Miller, and Blanco are considered analogous to the claimed invention as all are involved in the treatment of patients who are critically ill. Therefore, it would have been prima facie obvious to one of ordinary skill in the art the time of the effective filing date of the instant application to treat acute kidney injury using the injectable emulsion of CM4620 of Miller as Basile demonstrates that calcium signaling inhibitors, specifically those which inhibit CRAC, SOC, STIM1, Orai1, and ORai2, are useful for the treatment of acute kidney disease. Basile further states that an exemplary SOCE inhibitor to practice the invention is CM4620, with Miller demonstrating that this compound is useful in the prevention of the development of acute kidney injury in critically ill patients, providing both a motivation and reasonable expectation of success in selecting this specific inhibitor. The use of CM4620 for the treatment of acute kidney injury, in view of the teachings of Basile and Miller, is prima facie obvious combination of prior art elements according to known methods to yield predictable results (See MPEP § 2143 I (A)); Basile teaches the use of SOCE inhibitors for the treatment of AKI, with an exemplary inhibitor being CM4620, while Miller demonstrates that this compound is useful for the prevention of AKI in critically ill patients, and thus, the artisan would be motivated to select this specific compound as it is both an exemplary inhibitor provided by Basile, with Miller demonstrating efficacy in the prevention of AKI.
Regarding the once daily administration, dosage adjustments in patients which have AKI are known in the art of pharmaceutics as taught by Blanco. The administration of the injectable emulsion of once daily for the treatment of AKI would be obvious to one of ordinary skill in the art in view of what is taught by Blanco. AKI results in reduced clearance of drug due to alterations in metabolism and elimination, as well as increased free drug due to alterations in serum albumin. These combine to result in an increased half-life of the drug. Thus, the artisan would expect that a single administered dose would be sufficient to treat AKI. The artisan would be capable of tailoring the specific amount delivered in this single dose to ensure that the appropriate serum level of drug is achieved to result in a treatment for AKI.
Regarding Claims 4-8, CM4620 inherently possesses these properties, and as such, when administered, will inhibit each of these channels.
Regarding Claims 24 and 25, the data presented by Miller demonstrate a reduction in AKI, and thus provide a reasonable expectation of success that the use of this method would be effective in the treatment of each stage of AKI. This reduction also provides a motivation and reasonable expectation of success in applying this method in patients who are at risk of developing chronic kidney disease or end-stage renal disease due to the demonstrated efficacy in preventing AKI.
Conclusion
Claims 1, 4-8, 12-14, 24, and 25 are rejected.
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/P.M.R./Examiner, Art Unit 1625
/JOHN S KENYON/Primary Patent Examiner, Art Unit 1625
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