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
In the amendment filed January 26, 2023, is a national stage entry under 35 U.S.C. s 371 of International Patent Application No. PCT/US2021/043230, filed July 26, 2021, which claims priority to U.S. Provisional Patent Application No. 63/056,706, filed July 26, 2020
Status of the Claims
In the amendment filed October 8, 2025, claims 2-4, 9, and 14-15 are canceled; and claims 1, 5-8, and 10-13 are amended. Claims 1, 5-8, 10-13, and 16 are currently pending.
Previous Rejections and/or Objections
Any objections and/or rejections raised in the previous Office Action but not reiterated below are considered to have been withdrawn.
Claim Rejections - 35 USC § 103 – Modified in View of Amendment, Maintained
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, 5-8, 10-13, and 16 are obvious over Melton and Abe:
Claims 1, 5-8, 10-13, and 16 are rejected under 35 U.S.C. § 103 as being unpatentable over U.S. Patent Application Publication No. 2015/0119399 to Melton et al. (hereinafter, “Melton”) in, in view of U.S. Patent No. 9,630,971 to Abe et al. (hereinafter, “Abe”).
Applicant traverses the previous rejections for obviousness, and argues in the main that, even if Melton generally teaches the combination of a PDE1 inhibitor and an SGLT2 inhibitor for the treatment of diabetes, Melton does not specifically teach a PDE1 inhibitor in the combination. For example, Applicant asserts that:
While paragraph [0050] provides a broad definition of “phosphodiesterase inhibitor”, such a definition does not constitute a teaching or suggestion of every isozyme in the class within the specific context of β-cell replication or growth and diabetes treatment, particularly where Melton elsewhere limits the scope to specific PDE isozymes-namely PDE3, PDE4, PDE5, and PDE11A Moreover, the Examiner's reliance on paragraphs [0056] and [0058] is misplaced. These paragraphs merely describe general biochemical properties of PDE1, such as its regulation by Ca2+/calmodulin (paragraph [0056]) and its dual substrate specificity (paragraph [0058]). Similarly, paragraph [0080] lists known PDE1 inhibitors, without linking them to β-cell function or diabetes treatment.
-pg. 14 of Applicant’s Remarks of October 8, 2025, first full non-quotation paragraph
Applicant further asserts that, on this basis (that Melton allegedly teaches the use of PDE inhibitors as a genus, but does not specifically teach the use of PDE1 inhibitors, a proper rejection must cite additional art that specifically teaches or suggests the use of PDE1 inhibitors for the treatment of diabetes (pg. 14, final paragraph through pg. 15, penultimate paragraph of Applicant’s Remarks).
These arguments have been fully considered but are not found persuasive.
On an initial ancillary matter, Applicant correctly points out that the difference between compound SCH51866 of Melton and instant Formula Ia is greater than was suggested in the previous Office Action (paragraph spanning the bottom of pg. 8 to the top of pg. 9 of Applicant’s Remarks). This greater difference between compound SCH51866 and instant Formula Ia has no bearing on the prima facie case of obviousness.
With respect to Applicant’s argument that the definition of Melton does not constitute a teaching of an inhibitor of every isozyme, the definition of paragraph [0050] clearly does cover an inhibitor of any phosphodiesterase isozyme. This definition of paragraph [0050] covers them generally (e.g. “any compound that inhibits or decreases the level or activity of a phosphodiesterase enzyme, isozyme, or allozyme”), rather then specifically listing various isozymes within this paragraph, but it clearly is intended to expressly include all isozymes, rather than merely including some isozymes.
With respect to the cited paragraphs [0056] and [0058], taken in context they appear to specifically teach PDE1 as an exemplary PDE subtype to be targeted in the disclosed method. Paragraph [0050] as noted, provides the general definition that includes inhibitors of all PDE subtypes and isozymes, and the ensuing paragraphs then discuss the properties and attributes of different exemplary isozymes. As such, the discussion of PDE1 in paragraphs [0056] and [0058] is not merely a discussion of the biochemical properties of PDE1, presented solely as disconnected background having no relevance to the disclosed invention; rather it is a specific mention of PDE1 as a PDE subtype to be targeted for inhibition during performance of the disclosed method.
Melton may not teach PDE1 inhibitors as a specifically preferred subtype of PDE inhibitors, but such express preference is not required to support a prima facie case of obviousness. Indeed, even if Melton expressly labeled PDE1 inhibitors as a non-preferred embodiment, which it does not, such a label would not defeat the prima facie case of obviousness (see MPEP 2123(II) and cases cited therein).
Melton teaches a method for treating a disorder such as diabetes comprising administering a PDE inhibitor (which can be a PDE1 inhibitor), optionally in combination with an SGLT2 inhibitor. As such, Melton does teach PDE1 inhibitors in the context of diabetes treatment. While it would be possible to cite additional art that focuses on the use of PDE1 inhibitors for the treatment of diabetes, or that discloses a connection between PDE1 inhibition and increased insulin secretion (see, for example, the non-patent publication, The Calcium/Calmodulin-dependent Phosphodiesterase PDE1C Down-regulates Glucose-induced Insulin Secretion, Cell. Biol. & Metab., 274, pgs. 22337-22344 (1999) by Han et al.), for all of the aforementioned reasons, this is not deemed necessary at this time to support the prima facie case of obviousness.
The rejections, while modified, are maintained in substance.
Modified, Maintained Rejection:
Claim 1 recites a method for the treatment and/or prophylaxis of a disease, disorder or condition associated with altered glucagon function and/or with altered cyclic nucleotide signaling, comprising administration of a pharmaceutically effective amount of a PDE1 inhibitor and a pharmaceutically effective amount of an active agent that increases circulating glucagon to a patient in need thereof.
Melton teaches, inter alia, methods of treating disorders such as diabetes (Abstract). Diabetes is a disease, disorder, or condition of instant claim 1 (see, for example, instant claim 8). Melton teaches that these methods can include a step of administering a phosphodiesterase inhibitor to a subject (paragraph [0174]) either as a monotherapy, or as a combination therapy with other pharmaceutically active agents (paragraph [0175]). Melton further teaches that the PDE inhibitor can be an inhibitor of any PDE isozyme (paragraph [0050]), such as PDE1 (paragraphs [0056] and [0058]), and that the other pharmaceutically active compound that can be utilized in combination therapy with a PDE inhibitor can be an SGLT2 inhibitor, i.e. a type of active agent that increases circulating glucagon (paragraph [0177]). Melton teaches that compounds should generally be administered in a therapeutically effective amount (paragraph [0160]), i.e. the amount of compound effective for producing a desired therapeutic effect, considered to be substantially the same as a pharmaceutically effective amount of claim 1 (paragraph [0246]).
Melton thus recognizes the utility of PDE1 inhibitors and of SGLT2 inhibitors in treating diabetes, and further recognizes the potential benefits of the combination of PDE inhibitors, such as PDE1 inhibitors, with SGLT2 inhibitors. Therefore, it would have been obvious to perform a method of treating diabetes (a disease, disorder, or condition of instant claim 1) comprising administration of a pharmaceutically effective a PDE1 inhibitor and a pharmaceutically effective amount of an SGLT2 inhibitor (an active agent that increases circulating glucagon) to a patient in need thereof.
Melton teaches that a suitable PDE1 inhibitor includes SCH-51866
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which is similar to compounds of instant Formula Ia (in Formula 1a, R10 can be C1-4 alkyl, but it does not explicitly allow haloalkyl). It would have been obvious, however, to use compounds of instant claim 9, such as compounds of Formula 1a, including specifically compounds of claim 10, because such compounds were known in the art to be effective PDE1 inhibitors. See, for example, Abe.
Abe teaches that the compound (6aR,9aS)-5,6a,7,8,9,9a-hexahydro-5-methyl-3-(phenylamino)-2-((4-(6-fluoropyridin-2-yl)phenyl)methyl)-cyclopent[4,5]imidazo[1,2-a]pyrazolo[4,3-e]pyrimidin-4(2H)-one is a potent and selective PDE1 inhibitor (col. 1, lines 23-28)
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.
The compound of Abe is a compound of instant Formula 1a where R2 and R5 are H and R3 and R4 together form a trimethylene bridge; R6 is phenylamino; and R10 is pyridyl substituted with halogen. The compound of Abe is also the first listed PDE1 inhibitor of instant claim 10. It would have been obvious to utilize the potent and selective PDE1 inhibitor of Abe as the PDE inhibitor in the combination therapy of Melton for treating diabetes.
With respect to claim 5, diabetes is a metabolic condition, disease, or disorder. See, for example, the non-patent publication, Review on Prediction of Diabetes using Data Mining Technique, Int. J. Res. Sci. Innov., IV, pgs. 43-46 (2017) by Balpande et al., which states that diabetes is a metabolic disease where the improper management of blood glucose levels led to risk of many diseases like heart attack, kidney disease, eye etc. (Abstract).
With respect to claims 6-7, the instant specification states at paragraph [0066] that the word “treatment” includes treatment of the cause of a disease. Therefore treatment of hypertension associated with diabetes (claim 6) and a renal disorder consequent to diabetes (claim 7) is also achieved by treating the underlying diabetes as taught by Melton. With respect to claim 8, Melton teaches that the method is suitable for treatment of type 1 or type 2 diabetes, i.e. type 1 diabetes mellitus or type 2 diabetes mellitus (paragraph [0036]). With respect to claim 10, as noted, the compound of Abe, is the first PDE1 inhibitor recited therein.
With respect to claims 11-13, Melton explicitly teaches dapagliflozin as an example of a suitable SGLT2 inhibitor suitable for use in the combination therapy method (paragraph [0187]). With respect to claim 16, the claim does not require that the method be applied to a condition consequent to diabetes mellitus, but merely requires that if it is applied to such a condition, that the condition be selected from the specified group. Claim 16 is therefore obvious for the reason applied to claim 8, above. It is noted, however, that it would have been obvious to apply the method of Melton to a condition consequent to diabetes mellitus, such as nephropathy, because Melton teaches that the method is useful for delaying the onset of symptoms of diabetes like nephropathy (paragraph [0254]), and this is further consistent with the definition of “treating” in the instant claims, as discussed above in reference to claim 6-7. That is, per instant paragraph [0066], treating a nephropathy that is consequent to diabetes is achieved by treating the underlying diabetes.
Conclusion
THIS ACTION IS MADE FINAL. 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 ALEXANDER K SHOWALTER whose telephone number is (571)270-0610. The examiner can normally be reached M-F 9:00 am to 5:00 pm, eastern time.
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/ALEXANDER K. SHOWALTER/Examiner, Art Unit 1629
/JEFFREY S LUNDGREN/Supervisory Patent Examiner, Art Unit 1629
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