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, filed 10 November, 2022, is a national stage application of PCT/JP2021/017368, filed 6 May, 2021, which claims foreign benefit of Application JP2020-083163, filed 11 May, 2020.
Status of the Application
Receipt is acknowledged of Applicant’s claimed invention, filed 10 November, 2022, in the matter of Application N° 17/924,447. Said documents have been entered on the record.
Claims 33, 38, 40 and 46 are canceled. Claims 28-29, 34-37, 39, 41-45 and 47 are amended. No new matter was introduced.
Thus, Claims 28-32, 34-37, 39, 41-45 and 47-50 represent all claims currently under consideration.
Response to Amendment/Arguments
Claims 33, 38, 40 and 46 have been canceled. Therefore, the rejections of these claims under 35 U.S.C. 112(a), 101 and 103 are moot.
Applicant’s amendment is sufficient to overcome the rejection of Claims under 35 U.S.C. 112(b), 102(a)(1) and non-statutory Double Patenting.
With respect to the rejection under 35 U.S.C. §103, Applicant’s amendments have altered the scope of the claims such that the previous rejection is withdrawn. However, the amendments do not place the claims in condition for allowance. A new rejection under 35 U.S.C. §103, necessitated by the amendments, is set forth below.
Applicant's arguments regarding the rejection under 35 U.S.C. §101 have been fully considered but they are not persuasive.
Applicant argues that amended Claim 39 integrates the recited judicial exception into a practical application because the claim now requires administering a first dose of the compound, obtaining a sample after administration of the first dose, detecting the compound and recited metabolites, calculating an abundance ratio, and determining a second dose for administration to the Alzheimer patient based on the calculated abundance ratio. Applicant further argues that the claimed ordered combination amounts to significantly more than the judicial exception. (Remarks, Pg. 7-8).
The Examiner acknowledges that amended Claim 39 now expressly links the calculated abundance ratio to the determination of a second dose. However, Claim 39 does not require administration of the second dose so determined. Rather, the claim terminates with “determining a second dose…for administration to the Alzheimer’s patient based on the calculated abundance ratio.” Thus, although the detected metabolic information is used to determine a proposed subsequent dose, the claim does not require that the determined dose actually be administered to the patient.
The administration of the first dose does not cure this deficiency. The first dose is administered before the recited metabolite information is obtained and before the abundance ratio is calculated. Accordingly, the first administration does not apply the subsequently determined relationship to treatment of the patient. Instead, the first administration provides the biological condition from which the sample is obtained and the recited information concerning the compound and its metabolites is subsequently detected and analyzed. The claim therefore does not require that the patient be treated in accordance with the dosing determination resulting from the recited analysis.
This distinction is consistent with the treatment considerations discussed in MPEP §2106.04(d). A claim may integrate a judicial exception into a practical application where the recited relationship is affirmatively applied through a particular treatment, such as where information obtained from a patient is used to determine and administer a particular treatment to that patient. Here, Claim 39 requires determination of a second dose for administration, but does not require the determined second dose actually to be administered. The mere determination of a future treatment does not itself effect that treatment. Accordingly, the amendments to Claim 39 do not establish that the recited judicial exception is integrated into a practical application.
Applicant’s reliance on BASCOM Global Internet v. AT&T Mobility LLC is also not persuasive. Applicant’s argument concerning the claimed ordered combination (Remarks, Pg 8) has been considered in accordance with the eligibility set forth in MPEP §§ 2106.04(d) and 2106.05. As discussed above, the recited steps, considered both individually and in combination, do not require that the dosing determination resulting from the calculated abundance ratio be applied by administering the determined second dose to the patient. Accordingly, Applicant’s characterization of the ordered combination as non-conventional does not alter the conclusions that Claim 39 fails to integrate the recited judicial exception into a practical application.
Further, to the extent Applicant relies upon the ordered combination as providing “significantly more” under Step 2B, the additional elements are considered both individually and as an ordered combination in accordance with MPEP §2106.05. The eligibility determination, however, is based on the limitations actually recited in the claim. As discussed above, the claimed combination terminates with determining a second dose for administration and does not require administration of that determined dose. Accordingly, Applicant’s arguments concerning the ordered combination do not overcome the rejection.
Claims 41-45 further limit the compound, timing of detection, measurement of relative amounts, mass-spectrometric analysis, and/or calculation of the abundance ratio. However, none of these additional limitations requires administration of the second dose determined based on the calculated abundance ratio. Accordingly, Claims 41-45 do not remedy the deficiency discussed above with respect to Claim 39.
Claim 47 does not remedy the deficiency discussed above with respect to Claim 39. Claim 47 incorporates the method of Claim 39 and additionally recites “administering the compound or salt thereof to the Alzheimer’s patient after the detecting.” However, Claim 47 does not require that the compound subsequently administered be administered at the second dose determined in Claim 39 based on the calculated abundance ratio. Thus, although Claim 47 add a subsequent administration step, the claim does not require the administration to implement the patient-specific dosing determination resulting from the recited metabolite analysis. The claim therefore does not affirmatively require application of the calculated abundance ratio through administration of the dose determined therefrom.
This is distinguishable from a claim requiring that a dose be determined based on patient-specific information and that the dose so determined subsequently be administered to the patient. Neither Claim 39 nor Claim 47 requires that complete treatment relationship.
Claims 48-50 further limit the total dose administered relative to specified standard doses, but likewise do not require administration of the second dose determined based on the calculated abundance ratio. Therefore, these additional limitations do not remedy the foregoing deficiency.
Accordingly, Applicant’s amendments and arguments do not establish that Claims 39, 41-45 and 47-50 recite patent-eligible subject matter. As discussed below, Claims 39, 41-45 and 47-50 remain subject to rejection under 35 U.S.C. §101.
Below can be found new grounds of rejection necessitated by amendments.
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.
Claim 47 is 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.
Claim 47 recites “[a] method of treating an Alzheimer patient, comprising detecting the compound according to Formula I or salt thereof, 3,4-dehydrocilostazol and 4'-hydroxycilostazol in the Alzheimer patient in accordance with the method of claim 39:” and subsequently recites “administering the compound or salt thereof to the Alzheimer patient after the detecting.”
The manner in which Claim 47 references Claim 39 renders the scope of Claim 47 unclear. Claim 39 is directed to a “method of detecting 3,4-dehydrocilostazol in an Alzheimer patient,” but is not limited to a detecting step. Rather, Claim 39 recites a sequence of limitations including administering a first dose, obtaining a sample after administration of the first dose, detecting the compound the compound and recited metabolites by mass spectrometry, calculating an abundance ratio, and determining a second dose based on the calculated abundance ratio. Claim 47, however, does not conventionally recite the method of Claim 39 and further limit that method. Instead, Claim 47 recites its own “method of treating” and states that the recited detecting is performed “in accordance with the method of Claim 39.” Accordingly, it is unclear whether Claim 47 incorporates all limitations of the method of Claim 39, including the first-dose administration, sample acquisition, abundance ratio calculation, and second-dose determination, or whether the reference to Claim 39 is intended to modify only the detecting recited in Claim 47.
The ambiguity is further compounded by the recitation of administering the compound “after the detecting.” Claim 39 recites multiple detecting operations directed to the compound, 3,4-dehydrocilostazol, and 4'-hydroxycilostazol, respectively. It is therefore unclear which detecting operation is referenced by “the detecting” and, consequently, which claimed event must precede the administration recited in Claim 47.
Thus, the unconventional manner in which Claim 47 references the method of Claim 39, together with the ambiguous reference to “the detecting,” creates uncertainty as to which limitations of Claim 39 are incorporated into Claim 47 and the required relationship among the recited method steps. Accordingly, the metes and bounds of Claim 47 cannot be determined with reasonable certainty. See MPEP §§2173.02 and 2173.05(f).
For purposes of examination: Claim 47 is interpreted as incorporating all limitations of Claim 39 and as further requiring administration of the compound or salt thereof to the Alzheimer patient after the recited detecting. The subsequently administered compound is not interpreted as necessarily being administered at the second dose determined in Claim 39 based on the calculated abundance ratio, because Claim 47 does not expressly require such a relationship.
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 28-32 and 34-37 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for administering the compound, detecting the compound and metabolites, and calculating an abundance ratio, does not reasonably provide enablement for determining a second dose across the scope encompassed by the claims. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
The specification does not establish what abundance-ratio values or ranges correspond to particular second doses or dose adjustments, nor does it provide a working example in which a calculated abundance ratio is used to determine and administer a second dose.
Considering the factors set forth in MPEP §2164.01(a) and In re Wands, substantial experimentation would therefore be required to practice the claimed dosing method across its scope. While the techniques for obtaining a biological sample, detecting cilostazol and its metabolites, and calculating an abundance ratio are adequately described and appear routine, the claimed relationship between that ratio and the second dose constitutes the operative dosing step and is not taught by the disclosure. The specification provides observational data from a limited number of subjects but does not provide sufficient guidance or working examples establishing how those data are to be converted into an individualized second dose. In view of the limited guidance and absence of working examples directed to the claimed dose-determination step, relative to the breadth of the claimed functional relationship and the unpredictability associated with patient-specific drug metabolism and therapeutic response, a person of ordinary skill in the art would be required to undertake undue experimentation to determine which second dose should result from a given abundance ratio.
Accordingly, considering the Wands factors as a whole, particularly the breadth of the claimed dose-determination relationship, the limited direction and absence of working examples directed to that relationship, the variability and unpredictability associated with patient-specific drug metabolism and therapeutic response, and the experimentation necessary to establish a relationship between a given abundance ratio and an appropriate second dose, the specification does not enable the full scope of the claimed method without undue experimentation.
Claim Rejections - 35 USC § 101
(MAINTAINED – updated based on amendment)
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 39, 41-45 and 47-50 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a natural phenomenon without significantly more.
Claim 39 recites a method comprising administering a first dose of a compound according to Formula I or a salt thereof to an Alzheimer patient; obtaining a biological sample form the patient after administration of the first dose; detecting the compound, 3,4-dehydrocilostazol, and 4'-hydroxycilostazol in the biological sample by mass spectrometry; calculating an abundance ratio based on the detected amounts; and determining a second dose of the compound for administration to the Alzheimer patient based on the calculated abundance ratio.
Claim 39 recites a judicial exception because the claim relies upon the relationship between the amount and/or relative abundance of the administered compound and its metabolites in the patient and the determination of an appropriate subsequent dose. The relationship between the metabolism of the administered compound in the patient, the resulting amounts or relative amounts of the compound and its metabolites, and the information conveyed by those amounts is a naturally occurring biological relationship, i.e., a law of nature/natural phenomena. See MPEP §2106.04.
The steps of detecting the compound and metabolites and calculating an abundance ratio observe and quantify that biological relationship, while the step of determining a second dose based on the calculated abundance ratio uses the information obtained from the relationship to determine a proposed subsequent dose.
The claim as a whole does not integrate the judicial exception into a practical application. Although Claim 39 requires administration of a first dose, that administration occurs before the biological sample is obtained, before the compound and metabolites are detected, before the abundance ratio is calculated, and before the second dose is determined. The first-dose administration therefore does not apply the subsequently determined biological relationship through treatment based on that relationship.
Further, although Claim 39 requires determining a second dose for administration based on the calculated abundance ratio, the claim does not require administration of the second dose so determined. Thus, the claim does not require that the patient actually be treated in accordance with the patient-specific dosing determination resulting from the detected compound/metabolite information. Rather, the claimed method terminates upon determining a subsequent dose for possible administration.
MPEP §2106.04(d) explains that a judicial exception may be integrated into a practical application where the claim affirmatively applies the exception through a particular treatment or prophylaxis. Here, however, Claim 39 does not require that the treatment determined from the calculated abundance ratio actually be administered to the patient. Accordingly, when considered as a whole, the additional elements do not integrate the recited natural relationship into a practical application. See MPEP §§2106.05 and 2106.05(d).
The additional steps of obtaining a biological sample, detecting the compound and metabolites by mass spectrometry, and mathematically calculating an abundance ratio constitute data-gathering and analytical activity used to observe and quantify the recited biological relationship. The specification describes the use of biological samples such as blood or plasma and identifies known analytical techniques, including LC-MS, LC-MS/MS, HPLC, and immunoassay, for determining the amounts of cilostazol and its metabolites (Instant Specification, Pg 11, Para 0040-0041). The use of such analytical techniques does not provide an improvement to the analytical technology itself; rather, the techniques are used according to their established functions to obtain the information upon which the dosing determination is based.
Likewise, considering the additional elements in combination does not transform the nature of the claim into patent-eligible subject matter. The ordered combination administers the first dose, obtains and analyzes a biological sample, calculates information reflecting the patient’s metabolism of the compound, and uses that information to determine a proposed subsequent dose. However, the claim stops short of requiring administration of the dose determined from that information. Accordingly, the additional elements, individually and as an ordered combination, do not amount to significantly more than the recited judicial exception.
Therefore, Claim 39 is directed to a judicial exception without additional elements sufficient to integrate the exception into a practical application or amount to significantly more than the exception and is not patent eligible under 35 U.S.C. 101.
Claims 41-45 depend from Claim 39 and further limit, inter alia, the identity of the compound, timing of detection, measurement of relative amounts of the compound and metabolites, use of mass spectrometry, and/or calculation of the abundance ratio. These additional limitations further specify the compound and manner in which the biological information is obtained or calculated, but do not require administration of the second dose determined based on the calculated abundance ratio. Accordingly, these additional limitations do not integrate the recited judicial exception into a practical application or otherwise provide significantly more than the exception for the reasons discussed above with respect to Claim 39.
As set forth above, with respect to the rejection under 35 U.S.C. 112(b), for purposes of examination Claim 47 is interpreted as incorporating all limitations of Claim 39 and as further requiring administration of the compound or salt thereof to the Alzheimer patient after the recited detecting. Claim 47 therefore adds an actual subsequent administration step.
However, Claim 47 does not require that the subsequently administered compound be administered at the second dose determined based on the calculated abundance ratio in Claim 39. The administration is required only to occur “after the detecting.” Thus, the claim does not require that the dosing determination resulting from the recited biological relationship be implemented in the treatment of the patient.
Accordingly, although Claim 47 adds a subsequent administration step, that step does not affirmatively apply the patient-specific dosing determination resulting from the calculated abundance ratio. The additional administration therefore does not remedy the deficiency discussed with respect to Claim 39 or otherwise integrate the recited judicial exception into a practical application. Considered individually and in combination with the remaining limitations, the additional elements likewise do not amount to significantly more than the judicial exception.
Claims 48-50 depend from Claim 47 and further limit the total dose administered relative to specified standard doses. Although these claims further constrain the amount administered, they likewise do not require that the administered dose be the second dose determined based on the calculated abundance ratio. Thus, the additional dose limitations do not establish the required relationship between the patient-specific biological information and the treatment actually administered and do not alter the eligibility analysis discussed above.
Accordingly, Claims 39, 41-45 and 47-50 are rejected under 35 U.S.C. 101.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 28-32, 34-37, 39, 41-45 and 47-50 are rejected under 35 U.S.C. 103 as being unpatentable over Hong (US Patent 7,825,130, of previous record) and Bramer et al. (Journal of Pharmaceutical and Biomedical Analysis. 26. 2001. 637–650), hereinafter Bramer, and further in view of Hiemke et al. (Pharmacopsychiatry 2011; 44:195-235), hereinafter Hiemke.
Regarding Claims 28-29 and 35-37, Hong teaches a method of treating an Alzheimer patient by administering a compound of Formula I or a salt thereof, wherein the particularly preferred compound is cilostazol (‘130, Col 3). Hong teaches that the disclosed compounds are useful as medicaments for cognitive disorders and Alzheimer’s disease and that cilostazol may contribute to reducing amyloid-beta deposition and improving behavior associated with Alzheimer’s dementia (‘130, Col 8). Hong further teaches repeated administration of cilostazol, with a usual adult dosage of 100-400 mg/day administered once or divided into several administrations, which may be administered in divided doses (‘130, Abstract, Col 3, Para 2-6.) Hong additionally demonstrates collecting blood samples after administration for concentration measurement (‘130, Col 7, Example 3).
Hong does not expressly teach, following administration of a first dose and prior to administration of a second dose, detecting the compound together with the recited cilostazol metabolites, determining an abundance ratio thereof, and determining a second dose based on the abundance ratio.
Bramer teaches a method for the simultaneous quantitative determination of cilostazol and three active metabolites, OPC-13015, OPC-13213, and OPC-13217, in human plasma using liquid chromatography/tandem mass spectrometry (LC/MS/MS). Bramer teaches extraction of cilostazol and the metabolites from human plasma followed by chromatographic separation and detection by tandem mass spectrometry and validates the method over a quantitative range of 5.0-1200 ng/mL for each analyte. Bramer further demonstrates acceptable specificity, accuracy, precision, sensitivity, and stability for quantitative determination of cilostazol and its metabolites in human plasma. Bramer explains that the increased sensitivity of the LC/MS/MS method was required for adequate pharmacokinetic evaluation of clinical studies (2001, Abstract, Table 5, and Conclusion).
Hiemke (2011) further teaches therapeutic drug monitoring (TDM) in which concentrations of a drug and its metabolites in a biological sample are determined and the resulting information is used to optimize dosing for an individual patient. Hiemke teaches that active metabolites may contribute to clinical effects and that even metabolite information may provide information regarding the patient’s metabolic state. Hiemke further teaches evaluation of metabolite-to-parent concentration ratios, and establishes a TDM process in which a drug is administered, a blood sample is obtained, drug and/or metabolite concentrations are measured and interpreted, and the resulting information is used in clinical decision making to continue or correct the subsequent dose. Hiemke further teaches that TDM results serve as a guide to proper dosing of the individual patient and describes TDM-guided dose titration following measurement and interpretation of drug concentrations. (2011, Abstract, Table 2, Figure 1, Pg 217 §Clinical Decision Making, and Figure 3).
It would have been obvious to one of ordinary skill in the art, before the effective filing date of the invention, to modify the cilostazol treatment method of Hong by quantitatively determining cilostazol and its circulating metabolites following administration, as taught by Bramer, and by using the relative amounts of the parent drug and metabolites, including an abundance ratio calculated therefrom, to determine a subsequent dose in accordance with the therapeutic-drug-monitoring teachings of Hiemke. Hong already teaches repeated administration of cilostazol for Alzheimer’s disease and measurement of cilostazol blood concentration; Bramer teaches simultaneous quantitative determination of cilostazol and its active metabolites in human plasma using LC/MS/MS for pharmacokinetic evaluation; and Hiemke teaches that measured parent-drug/metabolite information, including metabolite-to-parent concentration ratios, may be used in therapeutic drug monitoring to characterize patient-specific metabolism and guide subsequent dose adjustment. One of ordinary skill in the art therefore would have been motivated to apply the known TDM technique of Hiemke, using the cilostazol-specific analytical teachings of Bramer, to Hong’s cilostazol treatment method in order to account for patient-specific pharmacokinetic and metabolic variability and thereby individualize and optimize subsequent dosing.
It would have been obvious to express the quantitatively measured amounts of cilostazol and its metabolites as relative abundances and calculate the claimed abundance ratio therefrom. Bramer provides quantitative measurements of the individual parent drug and metabolites, while Hiemke expressly teaches the clinical utility of relative parent/metabolite concentration information, including metabolite-to-parent ratios. Calculation of the claimed relative abundance from the quantitatively measured species would therefore have represented a predictable mathematical use of the measured concentration data for the known purpose of characterizing the patient’s metabolic profile.
One of ordinary skill would also have had a reasonable expectation of success in making the proposed combination because Hong establishes repeated administration of cilostazol for Alzheimer’s disease and measurement of blood cilostazol concentration; Bramer establishes that cilostazol and its active metabolites can be simultaneously quantitatively measured in human plasma using a validated LC/MS/MS method suitable for pharmacokinetic evaluation; and Hiemke establishes therapeutic drug monitoring as a known process for using measured drug and metabolite information to guide individualized subsequent dosing. The proposed modification therefore applies known quantitative metabolic monitoring and dose-optimizing techniques to Hong’s known cilostazol treatment method to obtain the predictable result of a subsequent dose determined in view of the patient’s measured metabolic profile.
Regarding Claims 30-32, Hong further teaches administration of cilostazol at a daily dosage of 100-400 mg/day, administered once or divided into multiple administrations (‘130, Abstract, Col 3, Para 2-6). Thus, Hong expressly teaches total daily doses greater than the respective standard doses of 100 mg/day, 200 mg/day, and 300 mg/day recited in claims 30-32. Hiemke further teaches that therapeutic drug monitoring may be used to guide dose adjustment and that an increased dose, including a dose above a recommended dose, may be appropriate where measured drug concentrations indicate insufficient exposure at the standard dose (2011, Pg 217, §Clinical Decision Making). Accordingly, in carrying out the TDM-guided cilostazol treatment discussed above, it would have been obvious to select a total daily dose within Hong’s disclosed 100-400 mg/day range, including a total dose greater than the respective 100, 200, or 300 mg/day standard dose, where the patient’s measured drug/metabolite information indicated that an increased dose was appropriate. Such selection would have represented use of Hiemke’s known TDM-guided dose-adjustment technique within the dosage range expressly taught by Hong.
Regarding Claim 34, Hiemke further teaches that therapeutic drug monitoring is performed following administration of repeated doses to attain a steady-state drug concentration, which is generally achieved after approximately four to five elimination half-lives, and that for more than 90% of psychoactive medications steady state is reached within one week of maintenance dosing (2011, Pg 201, Para 2). Hiemke further teaches that, in clinical practice, the appropriate blood-sampling time for most psychoactive drugs is one week after stable daily dosing, immediately before administration of the next dose (2011, Pg 215, Col 2). Accordingly, it would have been obvious to obtain the biological sample and detect the recited compound and metabolites within one week after administration of the first dose when carrying out the TDM method discussed above, because Hiemke expressly teaches sampling within that time period for determination of drug concentrations used in dose optimization.
Regarding Claims 39, 41-45 and 47-50, Hong, Bramer and Hiemke teach the administration, biological sample analysis, quantitative drug/metabolite detection, therapeutic drug monitoring, abundance ratio, and subsequent dose determination limitations for the reasons discussed above. In particular, Bramer teaches simultaneous quantitative determination of cilostazol and its active metabolites in human plasma using LC/MS/MS, while Hiemke teaches use of drug and metabolite concentration information, including metabolite-to-parent concentration ratios, in therapeutic drug monitoring to guide individualized subsequent dosing. Accordingly, the findings and rationale set forth above regarding the combination of Hong, Bramer, and Hiemke are incorporated herein.
Conclusion
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.
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/D.M.N./ Examiner, Art Unit 1627
/SARAH PIHONAK/ Primary Examiner, Art Unit 1627
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