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 .
Application Status
The amendment filed on 12/12/2025 in response to the Non-Final Office action of 6/18/2025 is acknowledged and has been entered.
Claims 1, 7-11 and 17-20 are currently pending and under consideration.
Rejections withdrawn
The rejection of Claim(s) 1-2, 8-9, 11-12 and 18-19 under 35 U.S.C. 102(a)(1) as being anticipated by Andrew Levin (US20180360975A1, 12/20/2018) referred to here as “Levin”.
The rejection of Claim(s) 1-2, 8-9, 11-12 and 18-19 under 35 U.S.C. 102(a)(1) as being anticipated by Levin et al. (US20210353617A1, 11/18/2021, priority to 2018) referred to here as “Levin 2” is withdrawn in view of Applicants amendments.
The rejection of Claim(s) 3-7, 10, 13-17, 20 under 35 U.S.C. 103 as being unpatentable over Andrew Levin (US20180360975A1, 12/20/2018) referred to here as “Levin”, as applied above to claims 1-2, 8-9, 11-12 and 18-19, in view of McClellan and Plosker (Drugs 1999 58(1) 143-157) is withdrawn in view of Applicants amendments.
The rejection of Claim(s) 3-7, 10, 13-17, 20 under 35 U.S.C. 103 as being unpatentable over Levin et al. (US20210353617A1, 11/18/2021, priority to 2018) referred to here as “Levin 2”, as applied above to claims 1-2, 8-9, 11-12 and 18-19, in view of McClellan and Plosker (Drugs 1999 58(1) 143-157) is withdrawn in view of Applicants amendments.
The rejection of Claim(s) 1-20 under 35 U.S.C. 103 as being unpatentable over Levin et al. (US2022/0168431A1, 6/2/2022, priority to 2019) referred to here as “Levin 3” in view of McClellan and Plosker (Drugs 1999 58(1) 143-157) is withdrawn in view of Applicants amendments.
The rejection of Claims 1-6, 8, 11-16, 18 on the ground of nonstatutory double patenting as being unpatentable over at least claims 1-5 and 9 of U.S. Patent No. 11,969,422B2 to Patel et al. (2024-04-30) or claims 1, 3-4, 9 of U.S. Patent No. 11,793,807B2 to Patel et al. (2023-10-24) or claims 1-4, 9 of U.S. Patent No. 11,730,733 to Patel et al. (2023-08-22) or claims 1-4, 9 of U.S. Patent No. 12,076,318 to Patel et al. (2024-11-03) is withdrawn in view of Applicants filing of a Terminal Disclamainer.
The rejection of Claims 1-19 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 11 of copending Application No. 17/359,714 in view of McClellan and Plosker (Drugs 1999 58(1) 143-157) is withdrawn in view of the filing of a Terminal Disclaimer.
The rejection of Claims 1-20 are rejected on the ground of nonstatutory double patenting as being unpatentable over at least claims 1-5 of U.S. Patent No.10,953,102 to Levin (2021-03-23) in view of McClellan and Plosker (Drugs 1999 58(1) 143-157) in view of Applicants amendments.
The rejection of Claims 1-19 are rejected on the ground of nonstatutory double patenting as being unpatentable over at least claims 1-2, 4 of U.S. Patent No. 12,318,382B2 to Levin et al. (2005-06-03) in view of McClellan and Plosker (Drugs 1999 58(1) 143-157) in view of Applicants amendments.
The rejection of Claims 1-19 on the ground of nonstatutory double patenting as being unpatentable over claims 1-4, 6-7, 9, 11-13 and 17 of copending Application No. 17/439,763 in view of McClellan and Plosker (Drugs 1999 58(1) 143-157) in view of Applicants amendments.
New Rejections Necessitated by Applicants Amendment
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 7 and 17 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.
Both claim 7 and 17 recite the limitation "…wherein the at least one dose is provided daily ….". However, there is insufficient antecedent basis for this limitation in the claim, since claim 1 and claim 11 requires administration of two (2) doses per day For purposes of prior art, the examiner will interpret this as the administration of two doses per day.
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 1, 7-11 and 17-20 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. THIS IS A NEW MATTER REJECTION.
Claims 1 and 11 have been amended to recite that the “… at least one dose of a modified release tablet of a composition comprising a compound of formula (X)….” (underline to show amendment). Applicants contend that support for the amendment of claim 1 can be found throughout Applicant’s as filed application, for example as provided in the Published application (0020230210845), at least [0148], [0223], [0947], [0981], and Fig. 47. While the examiner has reviewed the specification as filed including the specific paragraphs pointed out by Applicants, it does not appear that any of these sections specifically provide support for a modified release tablet of a composition comprising a compound of formula (X). For example, the specific paragraphs cited by Applicants appear to provide support for a composition comprising 200 mg of the compound of formula X given orally BID, wherein the composition seems to be an immediate-release formulation (see paragraphs 0412 and 0518). The only reference to a modified release formulation is found in paragraph 0519 when discussing adding to the SAD part testing a single 35 mg modified release dose of trimetazidine (Vastarel). As such, the specification does not appear to provide support for a modified release tablet of a composition comprising a compound of formula (X).
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.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
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.
Claim(s) 1, 7-9, 11 and 17-19 is/are rejected under 35 U.S.C. 103 as being unpatentable over Andrew Levin (US20180360975A1, 12/20/2018) referred to here as “Levin” in view of Sisakian et al. (Heart Metab. 2009; 42: 25-28).
Levin teaches a method of treating a disease, disorder or condition in a patient comprising providing to the subject a compound represented by the formula (VII)
A-C (VII),
wherein:
A comprises a compound that shifts cardiac metabolism from fatty acid oxidation to glucose oxidation; and
C is a NAD+ precursor molecule (Claim 27 of Levin). With regards to the compound of formula (VII), Levin teaches that C is covalently linked to A, A is PEGylated with an ethylene glycol moiety, the covalent linkage is via the ethylene glycol moiety, A includes but is not limited to, trimetazidine and C includes but is not limited to nicotinic acid (Claims 30-37 of Levin). Specifically, Levin teaches a compound represented by formula (X):
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(also referred to as CV-8972 in Levin), which is identical to the compound of the instant claims (claim 41 of Levin). Moreover, Levin teaches that trimetazidine can cause Parkinsonian symptoms in a portion of the population so it is believed that delivery of trimetazidine as a component of a larger molecule may improve its efficacy and mitigate its side effects (column 0007). With regards to the conditions, Levin teaches that conditions include, but are not limited to:
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(claim 29 of Levin). Levin further provides the metabolism of compounds in Dogs (Starting at paragraph 0266). In particular, Levin teaches graphical information on the levels of trimetazidine (an analyte) after oral administration of CV-8972 at 1.5 mg/kg and levels of CV-8814 (an analyte) after oral administration of CV-8972 (Figures 60-61 and Table 58).
Levin does not specifically teach that CV-8972 is in the form of a modified release tablet or that the tablet comprises about 200 mg of CV-8972 and is giving orally twice a day, where in the amount is provided daily for at least two weeks.
Sisakian et al. teach a modified release formulation of trimetazidine, Vastarel MR, which has been shown to be useful in patients with stable angina at 35 mg Vastarel (page 26, 1st column, 3rd full paragraph). Specifically, Sisakian et al. teach that studies suggest that the modified-release formulation of trimetazidine may be more effective that the immediate release formulation with respect to relief of angina (page 26, 2nd column, bridging paragraph). In addition to treating angina, Sisakian et al. teach that a daily dose of 70 mg of modified-release trimetazidine is effective in treating ischemic cardiomyopathy (page 27, column 1, 1st full paragraph).
It would have been prima facie obvious to one of ordinary skill in the art, prior to the effective filing date of the instantly claimed invention, to provide CV-8972 taught by Levin in the form of a modified release formulation in view of the teachings of Sisakian et al.. One of ordinary skill in the art would have been motivated to make such a modification, with a reasonable expectation of success, because:
-Levin teaches that compound (X) is metabolized to trimetazidine and compound X is used in a method of treating cardiovascular conditions, and
- Sisakian et al. teach that studies suggest that the modified-release formulation of trimetazidine may be more effective that the immediate release formulation with respect to relief of angina.
Moreover, it would have been prima facie obvious to one of ordinary skill in the art, prior to the effective filing date of the instantly claimed invention, to optimize the dose to about 200 mg and the time period of administration of the compound taught by Levin . One of ordinary skill in the art would have been motivated to make such an optimization, with a reasonable expectation of success, because:
Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955).
While the examiner recognizes that the rejections have changed from the previous office action, the Examiner would like to address Applicants arguments page provided on page 7 of the response. In particular, Applicants assert that as compared to trimetazidine, the claimed composition and dosing regiments demonstrate rapid absorption, and extensive tissue distribution, which enhances therapeutic reach and onset of action as shown in paragraph 0519 of the specification. As a result, Applicants contend that the methods of the invention provide extended periods in which the metabolic products of the composition are maintained in the body above a therapeutic threshold without the side effects of conventional treatments such as trimetazidine.
These arguments have been considered, but are not found persuasive.
First, Applicants appear to insinuate that the results (the pharmacokinetic profile) shown in the instant specification are from those of the claimed composition which would be the modified release tablet. However, as noted in the New Matter rejection above, all the examples provided in the specification appear to use an immediate release tablet. As such, the results within the specification does not appear to be commensurate in scope with what is being claimed. Regarding the decrease in side effects, this would appear to be expected since Levin teaches delivery of trimetazidine as a component of a larger molecule may improve its efficacy and mitigate its side effects.
Claim(s) 10 and 20 is/are rejected under 35 U.S.C. 103 as being unpatentable over Andrew Levin (US20180360975A1, 12/20/2018) referred to here as “Levin” in view of Sisakian et al. (Heart Metab. 2009; 42: 25-28), as applied above to claims 1, 7-9, 11 and 17-19, in further view of McClellan and Plosker (Drugs 1999 58(1) 143-157).
The combination of Levin and Sisakian et al. has been applied above and incorporated herein.
The combination does not specifically teach that angina is refractory to other medical interventions.
McClellan and Plosker reviews the use of trimetazidine instable angina pectoris and other coronary conditions and has the following structure:
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(title and fig 1). With regards to the use of trimetazidine instable angina pectoris, the review teaches that the therapeutic efficacy of oral trimetazidine, both as a monotherapy and when used as an adjunctive therapy in patients with angina pectoris not sufficiently controlled by other antianginal agents, has been evaluated in a number of well-controlled clinical trials of up to 6 months duration (page 147, 1st column, last paragraph bridging 2nd column). For example, the review teaches that in the majority of the clinical trials trimetazidine was administered orally as a 20 mg dose 3 times daily (except for one study in which the dosage was titrated to 80mg/ day if necessary) for both monotherapy and combination therapy (page 147, 2nd column, 1st full paragraph). The review further teaches trimetazidine reduces the frequency of anginal attacks and nitroglycerin use in patients with angina pectoris when used as both monotherapy and combination therapy (page 148, 1st column, 1st paragraph and 2nd column, 3rd full paragraph). Lastly, the review article teaches that trimetazidine has a different mechanism of action from that of nitrates, beta blockers and calcium antagonists and therefore, is likely to be a useful adjunctive therapy in patients with angina pectoris refractory to other antianginal agents (page 155, 2nd column, 3rd full paragraph).
It would have been prima facie obvious to one of ordinary skill in the art, prior to the effective filing date of the instantly claimed invention, to treat an angina that is refractory to other medical interventions using the method taught by the combination in view of the teachings of McClellan and Plosker. One of ordinary skill in the art would have been motivated to make such substitution, with a reasonable expectation of success, because:
-McClellan and Plosker teaches that trimetazidine has a different mechanism of action from that of nitrates, beta blockers and calcium antagonists and therefore, is likely to be a useful adjunctive therapy in patients with angina pectoris refractory to other antianginal agents.
Claim(s) 1, 7-9, 11 and 17-19 is/are rejected under 35 U.S.C. 103 as being unpatentable over Levin et al. (US20210353617A1, 11/18/2021, priority to 2018) referred to here as “Levin 2” in view of Sisakian et al. (Heart Metab. 2009; 42: 25-28).
The applied reference has a common inventor with the instant application. Based upon the earlier effectively filed date of the reference, it constitutes prior art under 35 U.S.C. 102(a)(2).
This rejection under 35 U.S.C. 103 might be overcome by: (1) a showing under 37 CFR 1.130(a) that the subject matter disclosed in the reference was obtained directly or indirectly from the inventor or a joint inventor of this application and is thus not prior art in accordance with 35 U.S.C.102(b)(2)(A); (2) a showing under 37 CFR 1.130(b) of a prior public disclosure under 35 U.S.C. 102(b)(2)(B); or (3) a statement pursuant to 35 U.S.C. 102(b)(2)(C) establishing that, not later than the effective filing date of the claimed invention, the subject matter disclosed and the claimed invention were either owned by the same person or subject to an obligation of assignment to the same person or subject to a joint research agreement. See generally MPEP § 717.02.
Levin 2 teaches a method of treating a rheumatic disease, disorder or condition in a patient comprising providing to the subject a compound represented by formula (X):
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(also referred to as CV-8972 in Levin 2), which is identical to the compound of the instant claims (claim 39 of Levin 2). Moreover, Levin teaches that trimetazidine can cause Parkinsonian symptoms in a portion of the population so it is believed that delivery of trimetazidine as a component of a larger molecule may improve its efficacy and mitigate its side effects (paragraph 0005). With regards to the conditions, Levin teaches that conditions include, but are not limited to:
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(claim 49 of Levin 2). Furthermore, Levin 2 teaches that the composition is administered in a single unit dose (claim 41 of Levin 2), via oral administration (claim 42 of Levin 2). Levin 2 further provides the metabolism of compounds in Dogs (Starting at paragraph 0290). In particular, Levin 2 teaches graphical information on the levels of trimetazidine (an analyte) after oral administration of CV-8972 at 1.5 mg/kg and levels of CV-8814 (an analyte) after oral administration of CV-8972 (Figures 60-61 and Table 58). Please note: The active step of administering a compound of formula X in the method as described above is being interpreted as being at least one dose per.
Levin 2 does not specifically teach that CV-8972 is in the form of a modified release tablet or that the tablet comprises about 200 mg of CV-8972 and is giving orally twice a day, where in the amount is provided daily for at least two weeks.
Sisakian et al. teach a modified release formulation of trimetazidine, Vastarel MR, which has been shown to be useful in patients with stable angina at 35 mg Vastarel (page 26, 1st column, 3rd full paragraph). Specifically, Sisakian et al. teach that studies suggest that the modified-release formulation of trimetazidine may be more effective that the immediate release formulation with respect to relief of angina (page 26, 2nd column, bridging paragraph). In addition to treating angina, Sisakian et al. teach that a daily dose of 70 mg of modified-release trimetazidine is effective in treating ischemic cardiomyopathy (page 27, column 1, 1st full paragraph).
It would have been prima facie obvious to one of ordinary skill in the art, prior to the effective filing date of the instantly claimed invention, to provide CV-8972 taught by Levin 2 in the form of a modified release formulation in view of the teachings of Sisakian et al.. One of ordinary skill in the art would have been motivated to make such a modification, with a reasonable expectation of success, because:
-Levin 2 teaches that compound (X) is metabolized to trimetazidine and compound X is used in a method of treating cardiovascular conditions, and
- Sisakian et al. teach that studies suggest that the modified-release formulation of trimetazidine may be more effective that the immediate release formulation with respect to relief of angina.
Moreover, it would have been prima facie obvious to one of ordinary skill in the art, prior to the effective filing date of the instantly claimed invention, to optimize the dose to about 200 mg and the time period of administration of the compound taught by Levin . One of ordinary skill in the art would have been motivated to make such an optimization, with a reasonable expectation of success, because:
Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955).
Claim(s) 10 and 20 is/are rejected under 35 U.S.C. 103 as being unpatentable over Andrew Levin et al. (US20210353617A1, 11/18/2021, priority to 2018) referred to here as “Levin 2” in view of Sisakian et al. (Heart Metab. 2009; 42: 25-28), as applied above to claims 1, 7-9, 11 and 17-19, in further view of McClellan and Plosker (Drugs 1999 58(1) 143-157).
The combination of Levin 2 and Sisakian et al. has been applied above and incorporated herein.
The combination does not specifically teach that angina is refractory to other medical interventions.
McClellan and Plosker reviews the use of trimetazidine instable angina pectoris and other coronary conditions and has the following structure:
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(title and fig 1). With regards to the use of trimetazidine instable angina pectoris, the review teaches that the therapeutic efficacy of oral trimetazidine, both as a monotherapy and when used as an adjunctive therapy in patients with angina pectoris not sufficiently controlled by other antianginal agents, has been evaluated in a number of well-controlled clinical trials of up to 6 months duration (page 147, 1st column, last paragraph bridging 2nd column). For example, the review teaches that in the majority of the clinical trials trimetazidine was administered orally as a 20 mg dose 3 times daily (except for one study in which the dosage was titrated to 80mg/ day if necessary) for both monotherapy and combination therapy (page 147, 2nd column, 1st full paragraph). The review further teaches trimetazidine reduces the frequency of anginal attacks and nitroglycerin use in patients with angina pectoris when used as both monotherapy and combination therapy (page 148, 1st column, 1st paragraph and 2nd column, 3rd full paragraph). Lastly, the review article teaches that trimetazidine has a different mechanism of action from that of nitrates, beta blockers and calcium antagonists and therefore, is likely to be a useful adjunctive therapy in patients with angina pectoris refractory to other antianginal agents (page 155, 2nd column, 3rd full paragraph).
It would have been prima facie obvious to one of ordinary skill in the art, prior to the effective filing date of the instantly claimed invention, to treat an angina that is refractory to other medical interventions using the method taught by the combination in view of the teachings of McClellan and Plosker. One of ordinary skill in the art would have been motivated to make such substitution, with a reasonable expectation of success, because:
-McClellan and Plosker teaches that trimetazidine has a different mechanism of action from that of nitrates, beta blockers and calcium antagonists and therefore, is likely to be a useful adjunctive therapy in patients with angina pectoris refractory to other antianginal agents.
Claim(s) 1, 7-9, 11 and 17-19 is/are rejected under 35 U.S.C. 103 as being unpatentable over Levin et al. (US2022/0168431A1, 6/2/2022, priority to 2019) referred to here as “Levin 3” in view of Sisakian et al. (Heart Metab. 2009; 42: 25-28).
The applied reference has a common inventor with the instant application. Based upon the earlier effectively filed date of the reference, it constitutes prior art under 35 U.S.C. 102(a)(2). *
This rejection under 35 U.S.C. 103 might be overcome by: (1) a showing under 37 CFR 1.130(a) that the subject matter disclosed in the reference was obtained directly or indirectly from the inventor or a joint inventor of this application and is thus not prior art in accordance with 35 U.S.C.102(b)(2)(A); (2) a showing under 37 CFR 1.130(b) of a prior public disclosure under 35 U.S.C. 102(b)(2)(B); or (3) a statement pursuant to 35 U.S.C. 102(b)(2)(C) establishing that, not later than the effective filing date of the claimed invention, the subject matter disclosed and the claimed invention were either owned by the same person or subject to an obligation of assignment to the same person or subject to a joint research agreement. See generally MPEP § 717.02.
Levin 3 teaches a method of treating cancer in a patient comprising providing to the subject a compound represented by the formula (VII)
A-C (VII),
wherein:
A comprises a compound that shifts cardiac metabolism from fatty acid oxidation to glucose oxidation; and
C is a NAD+ precursor molecule (Claim 1 of Levin 3). With regards to the compound of formula (VII), Levin 3 teaches that C is covalently linked to A, A is PEGylated with an ethylene glycol moiety, the covalent linkage is via the ethylene glycol moiety, A includes but is not limited to, trimetazidine and C includes but is not limited to nicotinic acid (Claims 6-7, 9, 11-13 of Levin 3). Specifically, Levin 3 teaches a compound represented by formula (X):
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(also referred to as CV-8972 in Levin 3), which is identical to the compound of the instant claims (claim 17 of Levin 3). Moreover, Levin 3 teaches that trimetazidine can cause Parkinsonian symptoms in a portion of the population so it is believed that delivery of trimetazidine as a component of a larger molecule may improve its efficacy and mitigate its side effects (column 0005). Levin 3 further provides the metabolism of compounds in Dogs (Starting at paragraph 0305). In particular, Levin teaches graphical information on the levels of trimetazidine (an analyte) after oral administration of CV-8972 at 1.5 mg/kg and levels of CV-8814 (an analyte) after oral administration of CV-8972 (Figures 60-61 and Table 58).
Levin 3 does not specifically teach that CV-8972 is in the form of a modified release tablet or that the tablet comprises about 200 mg of CV-8972 and is giving orally twice a day, where in the amount is provided daily for at least two weeks.
Sisakian et al. teach a modified release formulation of trimetazidine, Vastarel MR, which has been shown to be useful in patients with stable angina at 35 mg Vastarel (page 26, 1st column, 3rd full paragraph). Specifically, Sisakian et al. teach that studies suggest that the modified-release formulation of trimetazidine may be more effective that the immediate release formulation with respect to relief of angina (page 26, 2nd column, bridging paragraph). In addition to treating angina, Sisakian et al. teach that a daily dose of 70 mg of modified-release trimetazidine is effective in treating ischemic cardiomyopathy (page 27, column 1, 1st full paragraph).
It would have been prima facie obvious to one of ordinary skill in the art, prior to the effective filing date of the instantly claimed invention, to provide CV-8972 taught by Levin 3 in the form of a modified release formulation in view of the teachings of Sisakian et al.. One of ordinary skill in the art would have been motivated to make such a modification, with a reasonable expectation of success, because:
-Levin 3 teaches that compound (X) is metabolized to trimetazidine and compound X is used in a method of treating cardiovascular conditions, and
- Sisakian et al. teach that studies suggest that the modified-release formulation of trimetazidine may be more effective that the immediate release formulation with respect to relief of angina.
Moreover, it would have been prima facie obvious to one of ordinary skill in the art, prior to the effective filing date of the instantly claimed invention, to optimize the dose to about 200 mg and the time period of administration of the compound taught by Levin 3. One of ordinary skill in the art would have been motivated to make such an optimization, with a reasonable expectation of success, because:
Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955).
Claim(s) 10 and 20 is/are rejected under 35 U.S.C. 103 as being unpatentable over Levin et al. (US2022/0168431A1, 6/2/2022, priority to 2019) referred to here as “Levin 3” in view of Sisakian et al. (Heart Metab. 2009; 42: 25-28), as applied above to claims 1, 7-9, 11 and 17-19, in further view of McClellan and Plosker (Drugs 1999 58(1) 143-157).
The combination of Levin 3 and Sisakian et al. has been applied above and incorporated herein.
The combination does not specifically teach that angina is refractory to other medical interventions.
McClellan and Plosker reviews the use of trimetazidine instable angina pectoris and other coronary conditions and has the following structure:
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(title and fig 1). With regards to the use of trimetazidine instable angina pectoris, the review teaches that the therapeutic efficacy of oral trimetazidine, both as a monotherapy and when used as an adjunctive therapy in patients with angina pectoris not sufficiently controlled by other antianginal agents, has been evaluated in a number of well-controlled clinical trials of up to 6 months duration (page 147, 1st column, last paragraph bridging 2nd column). For example, the review teaches that in the majority of the clinical trials trimetazidine was administered orally as a 20 mg dose 3 times daily (except for one study in which the dosage was titrated to 80mg/ day if necessary) for both monotherapy and combination therapy (page 147, 2nd column, 1st full paragraph). The review further teaches trimetazidine reduces the frequency of anginal attacks and nitroglycerin use in patients with angina pectoris when used as both monotherapy and combination therapy (page 148, 1st column, 1st paragraph and 2nd column, 3rd full paragraph). Lastly, the review article teaches that trimetazidine has a different mechanism of action from that of nitrates, beta blockers and calcium antagonists and therefore, is likely to be a useful adjunctive therapy in patients with angina pectoris refractory to other antianginal agents (page 155, 2nd column, 3rd full paragraph).
It would have been prima facie obvious to one of ordinary skill in the art, prior to the effective filing date of the instantly claimed invention, to treat an angina that is refractory to other medical interventions using the method taught by the combination in view of the teachings of McClellan and Plosker. One of ordinary skill in the art would have been motivated to make such substitution, with a reasonable expectation of success, because:
-McClellan and Plosker teaches that trimetazidine has a different mechanism of action from that of nitrates, beta blockers and calcium antagonists and therefore, is likely to be a useful adjunctive therapy in patients with angina pectoris refractory to other antianginal agents.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1, 7-9, 11 and 17-19 are rejected on the ground of nonstatutory double patenting as being unpatentable over at least claims 1-5 of U.S. Patent No.10,953,102 to Levin (2021-03-23) in view of Sisakian et al. (Heart Metab. 2009; 42: 25-28).
US Patent No 10,953,102 claims a method of increasing cardiac efficiency in a subject comprising providing to the subject a compound of formula (X), where the disease includes, but is not limited to, angina, the compound is provided orally (claims 1-5)
The US Patent does not claim that the compound is in the form of a modified release tablet or that the tablet comprises about 200 mg of the compound and is giving orally twice a day, where in the amount is provided daily for at least two weeks.
Sisakian et al. teach a modified release formulation of trimetazidine, Vastarel MR, which has been shown to be useful in patients with stable angina at 35 mg Vastarel (page 26, 1st column, 3rd full paragraph). Specifically, Sisakian et al. teach that studies suggest that the modified-release formulation of trimetazidine may be more effective that the immediate release formulation with respect to relief of angina (page 26, 2nd column, bridging paragraph). In addition to treating angina, Sisakian et al. teach that a daily dose of 70 mg of modified-release trimetazidine is effective in treating ischemic cardiomyopathy (page 27, column 1, 1st full paragraph).
It would have been prima facie obvious to one of ordinary skill in the art, prior to the effective filing date of the instantly claimed invention, to provide the compound claimed in the US Patent in the form of a modified release formulation in view of the teachings of Sisakian et al.. One of ordinary skill in the art would have been motivated to make such a modification, with a reasonable expectation of success, because:
- Sisakian et al. teach that studies suggest that the modified-release formulation of trimetazidine may be more effective that the immediate release formulation with respect to relief of angina.
Moreover, it would have been prima facie obvious to one of ordinary skill in the art, prior to the effective filing date of the instantly claimed invention, to optimize the dose to about 200 mg and the time period of administration of the compound claimed by the US Patent. One of ordinary skill in the art would have been motivated to make such an optimization, with a reasonable expectation of success, because:
Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955).
Claim(s) 10 and 20 are rejected on the ground of nonstatutory double patenting as being unpatentable over at least claims 1-5 of U.S. Patent No.10,953,102 to Levin (2021-03-23) in view of Sisakian et al. (Heart Metab. 2009; 42: 25-28), as applied above to claims 1, 7-9, 11 and 17-19, in further view of McClellan and Plosker (Drugs 1999 58(1) 143-157).
The combination of the US Patent and Sisakian et al. has been applied above and incorporated herein.
The combination does not specifically teach that angina is refractory to other medical interventions.
McClellan and Plosker reviews the use of trimetazidine instable angina pectoris and other coronary conditions and has the following structure:
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(title and fig 1). With regards to the use of trimetazidine instable angina pectoris, the review teaches that the therapeutic efficacy of oral trimetazidine, both as a monotherapy and when used as an adjunctive therapy in patients with angina pectoris not sufficiently controlled by other antianginal agents, has been evaluated in a number of well-controlled clinical trials of up to 6 months duration (page 147, 1st column, last paragraph bridging 2nd column). For example, the review teaches that in the majority of the clinical trials trimetazidine was administered orally as a 20 mg dose 3 times daily (except for one study in which the dosage was titrated to 80mg/ day if necessary) for both monotherapy and combination therapy (page 147, 2nd column, 1st full paragraph). The review further teaches trimetazidine reduces the frequency of anginal attacks and nitroglycerin use in patients with angina pectoris when used as both monotherapy and combination therapy (page 148, 1st column, 1st paragraph and 2nd column, 3rd full paragraph). Lastly, the review article teaches that trimetazidine has a different mechanism of action from that of nitrates, beta blockers and calcium antagonists and therefore, is likely to be a useful adjunctive therapy in patients with angina pectoris refractory to other antianginal agents (page 155, 2nd column, 3rd full paragraph).
It would have been prima facie obvious to one of ordinary skill in the art, prior to the effective filing date of the instantly claimed invention, to treat an angina that is refractory to other medical interventions using the method taught by the combination in view of the teachings of McClellan and Plosker. One of ordinary skill in the art would have been motivated to make such substitution, with a reasonable expectation of success, because:
-McClellan and Plosker teaches that trimetazidine has a different mechanism of action from that of nitrates, beta blockers and calcium antagonists and therefore, is likely to be a useful adjunctive therapy in patients with angina pectoris refractory to other antianginal agents.
Claims 1, 7-9, 11 and 17-19 are rejected on the ground of nonstatutory double patenting as being unpatentable over at least claims 1-2, 4 of U.S. Patent No. 12,318,382B2 to Levin et al. (2005-06-03) in view of Sisakian et al. (Heart Metab. 2009; 42: 25-28).
US Patent no 12,318,382 claims a method of treating rheumatic disease, disorder, or condition in a subject, the method comprising providing to the subject a composition comprising a compound of formula (X), in a single unit dose and for oral administration (claims 1-2, 4).
The US Patent does not claim that the compound is in the form of a modified release tablet or that the tablet comprises about 200 mg of the compound and is giving orally twice a day, where in the amount is provided daily for at least two weeks.
Sisakian et al. teach a modified release formulation of trimetazidine, Vastarel MR, which has been shown to be useful in patients with stable angina at 35 mg Vastarel (page 26, 1st column, 3rd full paragraph). Specifically, Sisakian et al. teach that studies suggest that the modified-release formulation of trimetazidine may be more effective that the immediate release formulation with respect to relief of angina (page 26, 2nd column, bridging paragraph). In addition to treating angina, Sisakian et al. teach that a daily dose of 70 mg of modified-release trimetazidine is effective in treating ischemic cardiomyopathy (page 27, column 1, 1st full paragraph).
It would have been prima facie obvious to one of ordinary skill in the art, prior to the effective filing date of the instantly claimed invention, to provide the compound claimed in the US Patent in the form of a modified release formulation in view of the teachings of Sisakian et al.. One of ordinary skill in the art would have been motivated to make such a modification, with a reasonable expectation of success, because:
- Sisakian et al. teach that studies suggest that the modified-release formulation of trimetazidine may be more effective that the immediate release formulation with respect to relief of angina.
Moreover, it would have been prima facie obvious to one of ordinary skill in the art, prior to the effective filing date of the instantly claimed invention, to optimize the dose to about 200 mg and the time period of administration of the compound claimed by the US Patent. One of ordinary skill in the art would have been motivated to make such an optimization, with a reasonable expectation of success, because:
Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955).
Claim(s) 10 and 20 are rejected on the ground of nonstatutory double patenting as being unpatentable over at least claims 1-2, 4 of U.S. Patent No. 12,318,382B2 to Levin et al. (2005-06-03) in view of Sisakian et al. (Heart Metab. 2009; 42: 25-28), as applied above to claims 1, 7-9, 11 and 17-19, in further view of McClellan and Plosker (Drugs 1999 58(1) 143-157).
The combination of the US Patent and Sisakian et al. has been applied above and incorporated herein.
The combination does not specifically teach that angina is refractory to other medical interventions.
McClellan and Plosker reviews the use of trimetazidine instable angina pectoris and other coronary conditions and has the following structure:
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207
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(title and fig 1). With regards to the use of trimetazidine instable angina pectoris, the review teaches that the therapeutic efficacy of oral trimetazidine, both as a monotherapy and when used as an adjunctive therapy in patients with angina pectoris not sufficiently controlled by other antianginal agents, has been evaluated in a number of well-controlled clinical trials of up to 6 months duration (page 147, 1st column, last paragraph bridging 2nd column). For example, the review teaches that in the majority of the clinical trials trimetazidine was administered orally as a 20 mg dose 3 times daily (except for one study in which the dosage was titrated to 80mg/ day if necessary) for both monotherapy and combination therapy (page 147, 2nd column, 1st full paragraph). The review further teaches trimetazidine reduces the frequency of anginal attacks and nitroglycerin use in patients with angina pectoris when used as both monotherapy and combination therapy (page 148, 1st column, 1st paragraph and 2nd column, 3rd full paragraph). Lastly, the review article teaches that trimetazidine has a different mechanism of action from that of nitrates, beta blockers and calcium antagonists and therefore, is likely to be a useful adjunctive therapy in patients with angina pectoris refractory to other antianginal agents (page 155, 2nd column, 3rd full paragraph).
It would have been prima facie obvious to one of ordinary skill in the art, prior to the effective filing date of the instantly claimed invention, to treat an angina that is refractory to other medical interventions using the method taught by the combination in view of the teachings of McClellan and Plosker. One of ordinary skill in the art would have been motivated to make such substitution, with a reasonable expectation of success, because:
-McClellan and Plosker teaches that trimetazidine has a different mechanism of action from that of nitrates, beta blockers and calcium antagonists and therefore, is likely to be a useful adjunctive therapy in patients with angina pectoris refractory to other antianginal agents.
Claims 1, 7-9, 11 and 17-19 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-4, 6-7, 9, 11-13 and 17 of copending Application No. 17/439,763 in view of Sisakian et al. (Heart Metab. 2009; 42: 25-28).
This is a provisional nonstatutory double patenting rejection.
The copending application claims a method of treating cancer in a patient comprising providing to the subject a compound represented by the formula (VII)
A-C (VII),
wherein:
A comprises a compound that shifts cardiac metabolism from fatty acid oxidation to glucose oxidation; and
C is a NAD+ precursor molecule. With regards to the compound of formula (VII), The copending application claims that C is covalently linked to A, A is PEGylated with an ethylene glycol moiety, the covalent linkage is via the ethylene glycol moiety, A includes but is not limited to, trimetazidine and C includes but is not limited to nicotinic acid. Specifically, the copending application claims a compound represented by formula (X):
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(also referred to as CV-8972 in the copending application), which is identical to the compound of the instant claims.
The copending application does not claim that the compound is in the form of a modified release tablet or that the tablet comprises about 200 mg of the compound and is giving orally twice a day, where in the amount is provided daily for at least two weeks.
Sisakian et al. teach a modified release formulation of trimetazidine, Vastarel MR, which has been shown to be useful in patients with stable angina at 35 mg Vastarel (page 26, 1st column, 3rd full paragraph). Specifically, Sisakian et al. teach that studies suggest that the modified-release formulation of trimetazidine may be more effective that the immediate release formulation with respect to relief of angina (page 26, 2nd column, bridging paragraph). In addition to treating angina, Sisakian et al. teach that a daily dose of 70 mg of modified-release trimetazidine is effective in treating ischemic cardiomyopathy (page 27, column 1, 1st full paragraph).
It would have been prima facie obvious to one of ordinary skill in the art, prior to the effective filing date of the instantly claimed invention, to provide the compound claimed in the copending application in the form of a modified release formulation in view of the teachings of Sisakian et al.. One of ordinary skill in the art would have been motivated to make such a modification, with a reasonable expectation of success, because:
- Sisakian et al. teach that studies suggest that the modified-release formulation of trimetazidine may be more effective that the immediate release formulation with respect to relief of angina.
Moreover, it would have been prima facie obvious to one of ordinary skill in the art, prior to the effective filing date of the instantly claimed invention, to optimize the dose to about 200 mg and the time period of administration of the compound claimed by the copending application. One of ordinary skill in the art would have been motivated to make such an optimization, with a reasonable expectation of success, because:
Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955).
Claim(s) 10 and 20 are rejected on the ground of nonstatutory double patenting as being unpatentable over at least claims 1-2, 4 of U.S. Patent No. 12,318,382B2 to Levin et al. (2005-06-03) in view of Sisakian et al. (Heart Metab. 2009; 42: 25-28), as applied above to claims 1, 7-9, 11 and 17-19, in further view of McClellan and Plosker (Drugs 1999 58(1) 143-157).
Claim(s) 10 and 20 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-4, 6-7, 9, 11-13 and 17 of copending Application No. 17/439,763 in view of Sisakian et al. (Heart Metab. 2009; 42: 25-28), as applied above to claims 1, 7-9, 11 and 17-19, in further view of McClellan and Plosker (Drugs 1999 58(1) 143-157).
This is a provisional nonstatutory double patenting rejection.
The combination of the copending application and Sisakian et al. has been applied above and incorporated herein.
The combination does not specifically teach that angina is refractory to other medical interventions.
McClellan and Plosker reviews the use of trimetazidine instable angina pectoris and other coronary conditions and has the following structure:
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79
207
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(title and fig 1). With regards to the use of trimetazidine instable angina pectoris, the review teaches that the therapeutic efficacy of oral trimetazidine, both as a monotherapy and when used as an adjunctive therapy in patients with angina pectoris not sufficiently controlled by other antianginal agents, has been evaluated in a number of well-controlled clinical trials of up to 6 months duration (page 147, 1st column, last paragraph bridging 2nd column). For example, the review teaches that in the majority of the clinical trials trimetazidine was administered orally as a 20 mg dose 3 times daily (except for one study in which the dosage was titrated to 80mg/ day if necessary) for both monotherapy and combination therapy (page 147, 2nd column, 1st full paragraph). The review further teaches trimetazidine reduces the frequency of anginal attacks and nitroglycerin use in patients with angina pectoris when used as both monotherapy and combination therapy (page 148, 1st column, 1st paragraph and 2nd column, 3rd full paragraph). Lastly, the review article teaches that trimetazidine has a different mechanism of action from that of nitrates, beta blockers and calcium antagonists and therefore, is likely to be a useful adjunctive therapy in patients with angina pectoris refractory to other antianginal agents (page 155, 2nd column, 3rd full paragraph).
It would have been prima facie obvious to one of ordinary skill in the art, prior to the effective filing date of the instantly claimed invention, to treat an angina that is refractory to other medical interventions using the method taught by the combination in view of the teachings of McClellan and Plosker. One of ordinary skill in the art would have been motivated to make such substitution, with a reasonable expectation of success, because:
-McClellan and Plosker teaches that trimetazidine has a different mechanism of action from that of nitrates, beta blockers and calcium antagonists and therefore, is likely to be a useful adjunctive therapy in patients with angina pectoris refractory to other antianginal agents.
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 BRANDON J FETTEROLF whose telephone number is (571)272-2919. The examiner can normally be reached M-F 6AM-4PM.
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/BRANDON J FETTEROLF/Primary Examiner, Art Unit 1626