DETAILED ACTION
The amendment and RCE filed on 02/18/2026 has been entered and fully considered. Claims 1-5, 8-9 and 13-27 are pending, of which claim 25-27 are newly added.
Response to Amendment
In response to amendment, the examiner maintains rejection over the prior art established in the previous Office 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 .
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.
Claim(s) 1-2, 4-5, 8-9 and 21 is/are rejected under 35 U.S.C. 103 as being unpatentable over Sestak et al. (Journal of Pharmaceutical and Biomedical Analysis, 2016) (Sestak).
Regarding claim 1 and 21, Sestak teaches a method for measuring a carfilzomib
concentration of a sample comprising carfilzomib comprising the steps of
diluting the sample with a diluent comprising water and 50% by volume acetonitrile to form an analytical sample (section 2.2); and
subjecting the analytical sample to high performance liquid chromatography (HPLC) to determine the carfilzomib concentration in the sample (section 2.3).
Sestak does not specifically teach 25-40% of acetonitrile by volume. However, Sestak teaches that the HPLC mobile phase starts at 35% of acetonitrile by volume, and ends at 35% of acetonitrile by volume as well (section 2.3). Since the percent volume of acetonitrile changes between 35% and 70% during the HPLC process, it would have been obvious to one of ordinary skill in the art to optimize the percent volume of acetonitrile by routine experimentation. The result is predictable.
Further, Sestak expressly discloses that the HPLC gradient begins at 35% acetonitrile and ramps to 70% (Section 2.3). It is a well-established practice in chromatographic method development that the diluent should be of equal or weaker elution strength than the starting mobile phase, to ensure proper peak shape and to avoid precipitation or poor chromatography.
Thus, a sample prepared with 20–40% acetonitrile diluent would match or fall below the initial mobile phase concentration (35%), ensuring compatibility and preventing fronting or peak distortion. The skilled artisan would have had a clear motivation to adjust the diluent into this very range as part of routine optimization.
Sestak teaches preparation of carfilzomib samples in aqueous acetonitrile and further teaches an HPLC gradient starting at approximately 35% acetonitrile and increasing to higher organic content. These disclosures demonstrate that solvent polarity and acetonitrile content directly affect solubility and chromatographic performance of carfilzomib. Accordingly, acetonitrile concentration constitutes a recognized result-effective variable.
The choice of diluent is not isolated from the choice of mobile phase. Rather, chromatographers routinely consider both together. The principle of solvent-matching is standard: samples diluted in a solvent stronger than the initial mobile phase can lead to distorted peaks, while samples diluted in weaker solvents integrate cleanly at the head of the column. This makes acetonitrile percentage a recognized, result-effective variable in both contexts.
Regarding claim 2, Sestak teaches that the sample is obtained from carfilzomib compounding (section 2.1).
Regarding claim 4, Sestak teaches that wherein the sample is a solubilization sample (section 2.2).
Regarding claim 5, Sestak teaches that wherein the sample is a post-dilution
sample (section 2.2).
Regarding 8-9, as has been discussed in regard to claim 1 above, it would have been obvious to one of ordinary skill in the art to optimize the percent volume of acetonitrile by routine experimentation. The result is predictable.
Claim(s) 3, 13-20 and 22-27 is/are rejected under 35 U.S.C. 103 as being unpatentable over Sestak et al. (Journal of Pharmaceutical and Biomedical Analysis, 2016) (Sestak) in view of Lewis et al. (WO 2013/169282, IDS) (Lewis).
Regarding claim 3, Sestak does not specifically teach that wherein the sample is obtained from a bulk lyophilization solution of carfilzomib.
However, a bulk lyophilization solution is a conventional way of concentrating a compound. For example, Lewis teaches that wherein the sample is obtained from a bulk lyophilization solution of carfilzomib (page 87, line 19-27). Thus, it would have been obvious to one of ordinary skill in the art to apply Sestak method to a sample obtained from a bulk lyophilization solution of carfilzomib. The result is predictable.
Regarding claim 25, Sestak teaches a method for measuring a carfilzomib
concentration of a sample comprising carfilzomib comprising the steps of
diluting the sample with a diluent comprising water and 50% by volume acetonitrile to form an analytical sample (section 2.2); and
subjecting the analytical sample to high performance liquid chromatography (HPLC) to determine the carfilzomib concentration in the sample (section 2.3).
Sestak does not specifically teach 25-40% of acetonitrile by volume. However, Sestak teaches that the HPLC mobile phase starts at 35% of acetonitrile by volume, and ends at 35% of acetonitrile by volume as well (section 2.3). Since the percent volume of acetonitrile changes between 35% and 70% during the HPLC process, it would have been obvious to one of ordinary skill in the art to optimize the percent volume of acetonitrile by routine experimentation. The result is predictable.
Further, Sestak expressly discloses that the HPLC gradient begins at 35% acetonitrile and ramps to 70% (Section 2.3). It is a well-established practice in chromatographic method development that the diluent should be of equal or weaker elution strength than the starting mobile phase, to ensure proper peak shape and to avoid precipitation or poor chromatography.
Thus, a sample prepared with 20–40% acetonitrile diluent would match or fall below the initial mobile phase concentration (35%), ensuring compatibility and preventing fronting or peak distortion. The skilled artisan would have had a clear motivation to adjust the diluent into this very range as part of routine optimization.
Sestak teaches preparation of carfilzomib samples in aqueous acetonitrile and further teaches an HPLC gradient starting at approximately 35% acetonitrile and increasing to higher organic content. These disclosures demonstrate that solvent polarity and acetonitrile content directly affect solubility and chromatographic performance of carfilzomib. Accordingly, acetonitrile concentration constitutes a recognized result-effective variable.
The choice of diluent is not isolated from the choice of mobile phase. Rather, chromatographers routinely consider both together. The principle of solvent-matching is standard: samples diluted in a solvent stronger than the initial mobile phase can lead to distorted peaks, while samples diluted in weaker solvents integrate cleanly at the head of the column. This makes acetonitrile percentage a recognized, result-effective variable in both contexts.
Sestak does not specifically teach that wherein the formulation sample comprises a sugar. However, Lewis teaches that wherein the formulation sample comprises carfilzomib and a sugar (page 2, lines 10). Lewis teaches that “In addition to increasing the solubility of a peptide proteasome inhibitor in solution, the formulations prepared by the methods provided herein result in pharmaceutical solutions having surprising stability.” (page 2, lines 10-13). It would have been obvious to one of ordinary skill in the art to include sugar in the formulation, in order to increase the solubility and stability of the pharmaceutical solution.
Regarding claim 13-14, 22 and 26, Sestak teaches that wherein the carfilzomib concentration is 1 mg/ml (section 2.2).
Lewis teaches that wherein the carfilzomib concentration is 5 mg/ml (page 87, line 23-24).
it would have been obvious to one of ordinary skill in the art to optimize the concentration of carfilzomib by routine experimentation.
Regarding claim 15 and 23, it is conventional to keep the temperature of the analytical sample at 2°C to 8 °C prior to HPLC analysis. For example, Lewis stores the sample at 5-25 °C (page 87, line 25-26)
Regarding claim 16 and 24, it is conventional to keep the temperature of the analytical sample is at room temperature prior to HPLC analysis. For example, Lewis stores the sample at 5-25 °C (page 87, line 25-26)
Regarding claim 17, Lewis teaches preparing a lyophilizate from the sample (page 87, line 26-27). Lyophilization, is commonly used to preserve materials, extend shelf life, and make substances easier to transport.
Regarding claim 18-20, a lyophilizate is a substance that has been freeze-dried, meaning it has been processed to remove water while frozen, resulting in a solid, often powder-like, form. Thus, the amount of carfilzomib depends on the volume/weight and purity of the lyophilizate.
Regarding claim 27, Lewis teaches that wherein the sugar comprises a cyclodextrin (page 2, line 10).
Response to Arguments
Applicant's arguments filed 02/18/2026 have been fully considered but they are not persuasive.
Applicant argues that (i) solvent matching has not been shown to be a result-effective variable, (ii) the HPLC method should not be conflated with sample preparation, and (iii) the application demonstrates unexpected results establishing criticality of the claimed diluent range. Applicant further asserts that new claims 25–27 reciting formulation samples comprising sugar distinguish over the art. These arguments have been considered but are not persuasive for the reasons below.
(1) Solvent Matching and Result-Effective Variable
Applicant contends that the cited art does not establish solvent matching as a result-effective variable and that diluent composition is not recognized as a parameter for optimization in carfilzomib HPLC analysis.
The Examiner disagrees. Sestak teaches preparation of carfilzomib samples in aqueous acetonitrile and further teaches an HPLC gradient starting at approximately 35% acetonitrile and increasing to higher organic content. These disclosures demonstrate that solvent polarity and acetonitrile content directly affect solubility and chromatographic performance of carfilzomib. Accordingly, acetonitrile concentration constitutes a recognized result-effective variable.
Routine optimization of solvent composition to achieve suitable solubility, stability, and chromatographic compatibility would have been within the ordinary skill of the art (MPEP § 2144.05). Even where prior art uses different solvent percentages, exploration of solvent composition within a continuum of aqueous-organic mixtures represents routine experimentation rather than inventive activity (In re Aller; In re Peterson). The absence of an explicit “trend” in the art does not negate recognition that solvent polarity influences analytical performance.
(2) Relationship Between Diluent and Mobile Phase
Applicant asserts that diluent and mobile phase are independent parameters and that Sestak’s eluent teachings would not motivate modification of the diluent .
While diluent and mobile phase are distinct components, they are interrelated aspects of a single chromatographic system. A skilled chromatographer would reasonably consider both together when developing an analytical method, particularly to ensure solubility and injection compatibility. The skilled artisan would therefore have been motivated to adjust diluent strength relative to the starting mobile phase to maintain analyte stability and chromatographic performance.
Applicant’s argument that heterogeneity arises prior to injection does not negate this rationale. Ensuring sample homogeneity and stability through solvent optimization is itself a routine analytical consideration. Thus, the recognition that solvent composition affects sample integrity further supports the conclusion that acetonitrile percentage is a parameter subject to routine optimization.
(3) Alleged Unexpected Results
Applicant relies on Figure 1, Figure 2, and Table 5 to argue that a dramatic loss of accuracy occurs above approximately 50% acetonitrile and that the claimed 25–40% range provides unexpected advantages.
The Examiner acknowledges the data but finds them insufficient to establish non-obviousness. The results identify an optimum region within a known continuum of aqueous-organic solvent compositions. Identification of an optimum or workable sub-range within a broader known range is ordinarily considered obvious absent persuasive evidence of criticality or unpredictability.
The data are limited to particular formulations and conditions and do not demonstrate that the alleged effect is unexpected across the full breadth of the claims. Moreover, the observation that solvent composition affects analyte solubility and measurement accuracy is consistent with routine chromatographic principles and therefore does not rise to the level of unexpected results sufficient to overcome the prima facie case (MPEP § 716; Pfizer v. Apotex).
(4) Newly Added Claims 25–27 (Formulation with Sugar)
Applicant argues that formulation samples containing sugar (e.g., cyclodextrin) render the claims non-obvious because the art does not recognize sensitivity of such formulations to diluent composition.
This argument is not persuasive. Lewis teaches that wherein the formulation sample comprises carfilzomib and a sugar (page 2, lines 10). Lewis teaches that “In addition to increasing the solubility of a peptide proteasome inhibitor in solution, the formulations prepared by the methods provided herein result in pharmaceutical solutions having surprising stability.” (page 2, lines 10-13). It would have been obvious to one of ordinary skill in the art to include sugar in the formulation, in order to increase the solubility and stability of the pharmaceutical solution.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to XIAOYUN R XU, Ph. D. whose telephone number is (571)270-5560. The examiner can normally be reached M-F 8am-5pm.
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/XIAOYUN R XU, Ph.D./Primary Examiner, Art Unit 1797
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