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 .
DETAILED ACTION
This Office Action is in response to Applicant’s Arguments and Amendment filed, 09/02/2025, wherein the Amendment amended claims 1 and 5, and cancelled claims 2, 6, 14, and 19-20.
Claims 1, 3-5, 7-13, and 15-18 are pending and examined on the merits herein.
REJECTIONS WITHDRAWN
The status for each rejection and/or objection in the previous Office Action is set out below.
Claim Objections
Applicant’s amendment to claim 5 is sufficient to overcome this objection.
35 U.S.C. § 102
Applicant’s amendment to claim 1 that adds species of ARI is sufficient to overcome this rejection.
REJECTIONS-MAINTAINED/MODIFIED
In view of the amendments and cancellation of the claims, the 35 USC § 103 rejection is modified.
Specifically independent claim 1 has been amended to add species of aldose reductase inhibitors, and independent claim 5 have has been amended to replace “said animal in need of such treatment” with - -mammal diagnosed with diabetes- -, and to add species of aldose reductase inhibitors.
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 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 factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1, 3-5, 7-13, and 15-18 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2017/223179 to Wasmuth (published 2017, IDS) in view of WO 2014/028042 to Rubinstein (published 2014, IDS), Kim (“Cardiovascular Risks of Probenecid Versus Allopurinol in Older Patient, Jn. of the Am. College of Cardiology, published 2018, PTO-892), and NIH National Cancer Institute, “Cardiovascular Disease,” published 01/21/2021, PTO-892).
Wasmuth teaches a method of treating diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, diabetic cardiomyopathy, cardiovascular disease, or myocardial infarction by administering 2-(3-((6-fluorobenzo[d]oxazol-2-yl)methyl)-4-oxo-3,4-dihydrothieno[3,4-d]pyridazine-1-yl)acetic acid (pgs. 72-74, claims 23, 30, 32-35, 39, and 42).
Wasmuth additionally teaches a composition comprising 2-(3-((6-fluorobenzo[d]oxazol-2-yl)methyl)-4-oxo-3,4-dihydrothieno[3,4-d]pyridazine-1-yl)acetic acid and a pharmaceutically acceptable carrier (pgs. 72-73, claims 23 and 27). Wasmuth teaches that 2-(3-((6-fluorobenzo[d]oxazol-2-yl)methyl)-4-oxo-3,4-dihydrothieno[3,4-d]pyridazine-1-yl)acetic acid can be administered alone or in combination with pharmaceutically acceptable carriers ([0132]).
Regarding claim 1, while Wasmuth teaches a composition comprising the aldose reductase inhibitor, 2-(3-((6-fluorobenzo[d]oxazol-2-yl)methyl)-4-oxo-3,4-dihydrothieno[3,4-d]pyridazine-1-yl)acetic acid and a pharmaceutically acceptable carrier, it differs from that of claim 1, in that it does not teach probenecid.
Rubinstein teaches a method of treating cardiac dysfunction or symptoms of cardiac dysfunction by administering probenecid (title; abstract; pg. 34, claim 1). Probenecid increases contractility in cardiac myocytes through dose dependent changes in myocyte calcium concentration and improves calcium handling by the cell. The effects mediated by probenecid do not induce cell death and are not associated with increased infarct size during simulated myocardial infarction, unlike clinically used sympathomimetics ([0064]). Probenecid acts as a positive inotrope in a murine model and normalizes the ejection fraction of heart failure. Like murine cardiac tissue, human cardiac tissue also includes TRPV2 ion channels that can be targeted to treat cardiac dysfunction or the symptoms of cardiac dysfunction, with probenecid ([0065]).
Rubinstein specifically teaches heart failure, cardiomyopathy, and systolic cardiac dysfunction, as the cardiac dysfunction ([0063], pg. 35, claims 11-12).
Kim teaches probenecid as having cardioprotective effects (pg. 995, Col. 1, last sentence).
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 add probenecid, to Wasmuth’s composition comprising 2-(3-((6-fluorobenzo[d]oxazol-2-yl)methyl)-4-oxo-3,4-dihydrothieno[3,4-d]pyridazine-1-yl)acetic acid and pharmaceutically acceptable carrier, to arrive at instant claims 1 and 2. One of ordinary skill in the art would have been motivated to make such an addition, with a reasonable expectation of success, because:
-Wasmuth teaches a method of treating cardiomyopathy by administering 2-(3-((6-fluorobenzo[d]oxazol-2-yl)methyl)-4-oxo-3,4-dihydrothieno[3,4-d]pyridazine-1-yl)acetic acid and a pharmaceutically acceptable carrier, wherein NIH defines cardiovascular disease as “A type of disease that affects the heart or blood vessels. . .The most common cardiovascular disease is coronary artery disease (narrow or blocked coronary arteries), which can lead to chest pain, heart attacks, or stroke. Other cardiovascular diseases include congestive heart failure, heart rhythm problems, congenital heart disease (heart disease at birth), and endocarditis” (pg. 1, NIH);
-Rubinstein teaches a method of treating cardiomyopathy by administering probenecid;
-Rubinstein teaches probenecid as increasing contractility in cardiac myocytes and improving calcium handling by the cell; and
-Kim teaches probenecid as having cardioprotective effects.
As such, an ordinary skilled artisan would have been motivated to make such an addition to predictably arrive at a more therapeutically effective and potent method of treating cardiovascular disease, and "It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980). See MPEP 2144.06.
Regarding claim 3, Rubinstein teaches a dosage of about 1mg/kg/day to about 100g/kg/day (pg. 34, claim 7). Thus, in a 60kg subject, the dosage is about 60 mg to about 6000 mg; in the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. See MPEP 2144.05
Rubinstein further teaches that when treating cardiac dysfunction or the symptoms of cardiac dysfunction, the therapeutically effective dose of probenecid is a dose that achieves levels of probenecid and its active metabolites in the plasma to increase the contractility of the heart such that the cardiac output is sufficient to alleviate at least some symptoms of cardiac dysfunction ([0066]).
Regarding claim 4, Wasmuth teaches administration of 1-1000mg/day of 2-(3-((6-fluorobenzo[d]oxazol-2-yl)methyl)-4-oxo-3,4-dihydrothieno[3,4-d]pyridazine-1-yl)acetic acid ([0131], [0156]), and in the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. See MPEP 2144.05
Wasmuth additionally teaches that any dosage listed may constitute an upper or lower dosage range, and may be combined with any other dosage to constitute a dosage range comprising an upper and lower limit, and that the precise dosage also depends on the route of administration and should be decided according to the judgement of the practitioner and each patient’s circumstances ([0156], [0159]).
Further regarding claims 3-4, the optimization of known amounts for known active agents is considered well within the competence level of an artisan of ordinary skill in the pharmaceutical sciences; it has been held that the selection of optimal parameters, such as amounts of active agents, to achieve a beneficial effect, is within the skill in the art of an ordinary artisan. See In re Boesch, 205 USPT 215 (CCPA 1980) and MPEP 2144.05.
Regarding claims 5, 7-8, 13, and 16-17, while Wasmuth teaches a method of treating diabetic cardiomyopathy by administering a composition comprising 2-(3-((6-fluorobenzo[d]oxazol-2-yl)methyl)-4-oxo-3,4-dihydrothieno[3,4-d]pyridazine-1-yl)acetic acid and a pharmaceutically acceptable carrier, it differs from that of instant claims 5, 7-8, 13, and 16-17, in that it does not teach probenecid.
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 add probenecid, to the method of treating diabetic cardiomyopathy of Wasmuth, by administering a composition comprising 2-(3-((6-fluorobenzo[d]oxazol-2-yl)methyl)-4-oxo-3,4-dihydrothieno[3,4-d]pyridazine-1-yl)acetic acid, and pharmaceutically acceptable carrier, to arrive at instant claims 5, 7-8, 13, and 16-17. One of ordinary skill in the art would have been motivated to make such an addition, with a reasonable expectation of success, because:
-Wasmuth teaches a method of treating diabetic cardiomyopathy by administering 2-(3-((6-fluorobenzo[d]oxazol-2-yl)methyl)-4-oxo-3,4-dihydrothieno[3,4-d]pyridazine-1-yl)acetic acid,
-Rubinstein teaches a method of treating cardiomyopathy by administering probenecid,
-Rubinstein teaches probenecid as increasing contractility in cardiac myocytes and improving calcium handling by the cell; and
-Kim teaches probenecid as having cardioprotective effects.
As such, an artisan having ordinary skill in the art would have been motivated to make such an addition to predictably arrive at a more therapeutically effective and potent method of treating diabetic cardiomyopathy, and "It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980). MPEP 2144.06
Regarding the mg/day amounts in claim 5:
-Wasmuth teaches administration of 1-1000 mg/day of 2-(3-((6-fluorobenzo[d]oxazol-2-yl)methyl)-4-oxo-3,4-dihydrothieno[3,4-d]pyridazine-1-yl)acetic acid ([0131], [0156]); in the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. See MPEP 2144.05. Wasmuth additionally teaches that any dosage listed may constitute an upper or lower dosage range, and may be combined with any other dosage to constitute a dosage range comprising an upper and lower limit, and that the precise dosage also depends on the route of administration and should be decided according to the judgement of the practitioner and each patient’s circumstances ([0156], [0159]).
-Rubinstein teaches a dosage of about 1mg/kg/day to about 100g/kg/day (pg. 34, claim 7). Thus, in a 60kg subject, the dosage is about 60mg to about 6000mg; in the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. See MPEP 2144.05. Rubinstein further teaches that when treating cardiac dysfunction or the symptoms of cardiac dysfunction, the therapeutically effective dose of probenecid is a dose that achieves levels of probenecid and its active metabolites in the plasma to increase the contractility of the heart such that the cardiac output is sufficient to alleviate at least some symptoms of cardiac dysfunction ([0066]); and
-the optimization of known amounts for known active agents is considered well within the competence level of an artisan of ordinary skill in the pharmaceutical sciences; it has been held that the selection of optimal parameters, such as amounts of active agents, to achieve a beneficial effect, is within the skill in the art of an ordinary artisan. See In re Boesch, 205 USPT 215 (CCPA 1980) and MPEP 2144.05.
Regarding claims 9 and 18, Rubinstein teaches probenecid as increasing the contractility of the heart such that the cardiac output is sufficient to alleviate at least some symptoms of cardiac dysfunction ([0066]). As such, the method of the combination of Wasmuth, Rubenstein, Kim and NIH, would treat cardiovascular complications associated with deficiencies in cardiac output. Moreover, Wasmuth teaches treating diabetic cardiomyopathy, and as evidenced by pg. 5 of the instant specification, the population of patients with diabetic cardiomyopathy includes those with abnormalities in LVEF and cardiac output.
Regarding claim 10-11, and 15, Wasmuth teaches oral, sublingual, buccal and other forms of administration ([0152]-[0153], [0159]).
Regarding claim 12, since the combination of Wasmuth, Rubinstein, Kim, and NIH teaches a composition comprising 2-(3-((6-fluorobenzo[d]oxazol-2-yl)methyl)-4-oxo-3,4-dihydrothieno[3,4-d]pyridazine-1-yl)acetic acid, probenecid, and pharmaceutically acceptable carrier, the compounds are administered simultaneously.
Response to Arguments
Prior to responding to the individual arguments, it is respectfully pointed out that Applicant’s arguments are directed toward the individual references when the rejection was made over a combination of references; one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
On pg. 6, Remarks, Applicant argues that “the mere fact that the purported prior art could have been modified or applied in a manner to yield applicants’ invention would not have made the modification or application obvious unless the prior art suggested the desirability of the modification.”
This argument has been fully considered, but is not found persuasive. As stated in the above rejection:
Regarding independent claim 1, 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 add probenecid, to Wasmuth’s composition comprising 2-(3-((6-fluorobenzo[d]oxazol-2-yl)methyl)-4-oxo-3,4-dihydrothieno[3,4-d]pyridazine-1-yl)acetic acid and pharmaceutically acceptable carrier, to arrive at instant claims 1 and 2. One of ordinary skill in the art would have been motivated to make such an addition, with a reasonable expectation of success, because:
-Wasmuth teaches a method of treating cardiomyopathy by administering 2-(3-((6-fluorobenzo[d]oxazol-2-yl)methyl)-4-oxo-3,4-dihydrothieno[3,4-d]pyridazine-1-yl)acetic acid and a pharmaceutically acceptable carrier, wherein NIH defines cardiovascular disease as “A type of disease that affects the heart or blood vessels. . .The most common cardiovascular disease is coronary artery disease (narrow or blocked coronary arteries), which can lead to chest pain, heart attacks, or stroke. Other cardiovascular diseases include congestive heart failure, heart rhythm problems, congenital heart disease (heart disease at birth), and endocarditis” (pg. 1, NIH);
-Rubinstein teaches a method of treating cardiomyopathy by administering probenecid;
-Rubinstein teaches probenecid as increasing contractility in cardiac myocytes and improving calcium handling by the cell; and
-Kim teaches probenecid as having cardioprotective effects.
As such, an ordinary skilled artisan would have been motivated to make such an addition to predictably arrive at a more therapeutically effective and potent method of treating cardiovascular disease, and "It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980). See MPEP 2144.06.
Regarding independent claim 5, 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 add probenecid, to the method of treating diabetic cardiomyopathy of Wasmuth, by administering a composition comprising 2-(3-((6-fluorobenzo[d]oxazol-2-yl)methyl)-4-oxo-3,4-dihydrothieno[3,4-d]pyridazine-1-yl)acetic acid, and pharmaceutically acceptable carrier, to arrive at instant claims 5, 7-8, 13, and 16-17. One of ordinary skill in the art would have been motivated to make such an addition, with a reasonable expectation of success, because:
-Wasmuth teaches a method of treating diabetic cardiomyopathy by administering 2-(3-((6-fluorobenzo[d]oxazol-2-yl)methyl)-4-oxo-3,4-dihydrothieno[3,4-d]pyridazine-1-yl)acetic acid,
-Rubinstein teaches a method of treating cardiomyopathy by administering probenecid,
-Rubinstein teaches probenecid as increasing contractility in cardiac myocytes and improving calcium handling by the cell; and
-Kim teaches probenecid as having cardioprotective effects.
As such, an artisan having ordinary skill in the art would have been motivated to make such an addition to predictably arrive at a more therapeutically effective and potent method of treating diabetic cardiomyopathy, and "It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980). MPEP 2144.06
Regarding the mg/day amounts in claim 5:
-Wasmuth teaches administration of 1-1000mg/day of 2-(3-((6-fluorobenzo[d]oxazol-2-yl)methyl)-4-oxo-3,4-dihydrothieno[3,4-d]pyridazine-1-yl)acetic acid ([0131], [0156]); in the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. See MPEP 2144.05. Wasmuth additionally teaches that any dosage listed may constitute an upper or lower dosage range, and may be combined with any other dosage to constitute a dosage range comprising an upper and lower limit, and that the precise dosage also depends on the route of administration and should be decided according to the judgement of the practitioner and each patient’s circumstances ([0156], [0159]).
-Rubinstein teaches a dosage of about 1mg/kg/day to about 100g/kg/day (pg. 34, claim 7). Thus, in a 60kg subject, the dosage is about 60mg to about 6000mg; in the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. See MPEP 2144.05. Rubinstein further teaches that when treating cardiac dysfunction or the symptoms of cardiac dysfunction, the therapeutically effective dose of probenecid is a dose that achieves levels of probenecid and its active metabolites in the plasma to increase the contractility of the heart such that the cardiac output is sufficient to alleviate at least some symptoms of cardiac dysfunction ([0066]); and
-the optimization of known amounts for known active agents is considered well within the competence level of an artisan of ordinary skill in the pharmaceutical sciences; it has been held that the selection of optimal parameters, such as amounts of active agents, to achieve a beneficial effect, is within the skill in the art of an ordinary artisan. See In re Boesch, 205 USPT 215 (CCPA 1980) and MPEP 2144.05.
Thus, the above rejection provides obviousness rationales that suggest “the desirability of the modification.”
On pg. 7, Remarks, Applicant argues that Rubenstein does not teach or suggest that its treatment of cardiac dysfunction is as a result of a diabetic complication, and thus, there is no motivation to combine Wasmuth and Rubenstein.
This argument has been fully considered, but is not found persuasive. Wasmuth teaches a method of treating diabetic cardiomyopathy and Rubenstein teaches a method of treating cardiomyopathy. The patient population of Wasmuth is diabetic patients with cardiomyopathy and the patient population of Rubenstein is any patient with cardiomyopathy. While the patient population of Wasmuth is a sub-population of the patient population of Rubenstein, both the patients in Wasmuth and those in Rubenstein suffer from cardiomyopathy. As such, it is reasonably expected that a method of treating patients with cardiomyopathy will treat patients with diabetic cardiomyopathy. Applicant has provided no evidence or data suggesting that diabetic cardiomyopathy is distinct from cardiomyopathy.
Applicant argues that Kim provides a retrospective analysis of comparative safety data on the use of probenecid and allopurinol in gout patients and argues that the reference neither teaches nor suggests that any of the patients were diagnosed with diabetes.
This argument has been fully considered, but is not found persuasive. Kim is not relied upon to teach a diabetic patient population. Kim is relied upon for its teaching that probenecid is known in the pharmaceutical arts to have cardioprotective effects, thereby bolstering the motivation to add the probenecid taught by Rubenstein to the methods of treating diabetic cardiomyopathy by administering 2-(3-((6-fluorobenzo[d]oxazol-2-yl)methyl)-4-oxo-3,4-dihydrothieno[3,4-d]pyridazine-1-yl)acetic acid, of Wasmuth.
For these reasons, Applicant’s arguments are not persuasive to overcome the instant rejections.
Conclusion
No claims are 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 LAUREN WELLS whose telephone number is (571)272-7316. The examiner can normally be reached M-F 7:00-4:30.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, James (Jim) Alstrum-Acevedo can be reached on 571-272-5548. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/L.Q.W./Examiner, Art Unit 1622
/JAMES H ALSTRUM-ACEVEDO/Supervisory Patent Examiner, Art Unit 1622