DETAILED ACTION
A non-final Office action was mailed 21 October 2025 (“Office Action”).
Applicant’s reply to the Office Action was received 20 January 2026 (“Reply”).
Status of the Claims
The listing of claims filed with the Reply has been examined.
Claims 1, 3–5, 21–27, and 30–36 are pending.
Claims 2, 6–20, 28, and 29 are canceled.
Claims 1 and 21–27 are amended. Claims 30–36 are new.
Status of Rejections and Objections
The text of those sections of Title 35, U.S. Code and/or text providing the basis for non-statutory double patenting rejections not included in this action are set forth in the Office Action.
Unless repeated herein, any objection or rejection in the Office Action is withdrawn.
Objections to the Specification
The specification is objected to because it does not recite paragraphs in consecutive order. For example, after ¶32 on page 6, the numbering restarts at ¶1.
Appropriate correction is required.
Claim Rejections - 35 U.S.C. § 112 and 35 U.S.C. § 132
The following is a quotation 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 35 U.S.C. § 132(a):
(a) Whenever, on examination, any claim for a patent is rejected, or any objection or requirement made, the Director shall notify the applicant thereof, stating the reasons for such rejection, or objection or requirement, together with such information and references as may be useful in judging of the propriety of continuing the prosecution of his application; and if after receiving such notice, the applicant persists in his claim for a patent, with or without amendment, the application shall be reexamined. No amendment shall introduce new matter into the disclosure of the invention.
Claim 33 is rejected under 35 U.S.C. § 112(a) as failing to comply with the written description requirement, and under 35 U.S.C. § 132(a) for introducing new matter. The claims contain subject matter that was not described in the Specification in such a way as to reasonably convey to one of ordinary skill in the art that Applicant, at the time the application was filed, had possession of the claimed invention. This is a new matter rejection.
Claim 33 recites: “The method of claim 1, wherein Compound 1 is administered in a form of a monohydrate.”
Claim 34 recites: “The method of claim 1, wherein Compound 1 is administered as a monohydrate crystalline form.”
Examiner interprets claims 33 and 34 as having a different scope relative to one another. In particular, Examiner interprets a monohydrate crystalline form in claim 34 to be a specific species/subgenus, and a form of a monohydrate in claim 33 to be a genus of monohydrate forms that includes but is not limited to the crystalline species in claim 34.
The specification mentions the word “monohydrate” once:
In some embodiments, the pharmaceutical composition comprises Compound 1 as the solvated, unsolvated, or crystalline/polymorph form. In some embodiments, Compound 1 is present as the unsolvated form. In some embodiments, Compound 1 is present as the solvated form. In some embodiments, Compound 1 is present as the crystalline form. In some embodiments, Compound 1 is present as the monohydrate crystalline form.
(Spec., p.10, ¶38 (filed 25 April 2023)) (emphasis added).
The above specification paragraph refers to the subject matter recited in claim 34.
There are no examples in the specification showing the preparation or characterization of a solvate (e.g., hydrate) or crystalline form thereof.
There is no support in the specification for the claimed genus of monohydrate forms recited in claim 33.
Examiner suggests that Applicant cancel the new matter in the reply to this Office Action.
Response to Remarks
Applicant asserts the newly added claims have support in the specification at ¶¶12, 44, 74, 76, and 78. (Remarks, p.8). None of the recited paragraphs mention monohydrate.
Claim Rejections - 35 U.S.C. § 103
Claims 1, 3–5, 21–27, and 30–36 are rejected under 35 U.S.C. § 103 as being unpatentable over US 2017/0173018 (“Svenstrup”) in view of Lee et al., Nature (2015), 519, 472–476 (“Lee”), WO 03/037899 (“Deninno”), Clinical Trial NCT00930059, available at https://clinicaltrials.gov/study/NCT00930059?term=NCT00930059&rank=1&tab=history&a=19#version-content-panel (9 April 2013) (“NCT00930059”), and Clinical Trial NCT0340112, available at https://clinicaltrials.gov/study/NCT03401112?term=IMR-687&rank=2&a=1 (9 January 2018) (“NCT0340112”).
The Graham factors are addressed in turn below.
Determining the scope and contents of the prior art
Svenstrup discloses PDE9 inhibitors having the structure of formula (I), including a salt, solvate, or prodrug thereof. (Svenstrup, ¶¶9–11; 15–39). Svenstrup discloses Compound 1. (Id., p.7 (Table 1); claims 1 and 4). Svenstrup discloses formulating the PDE9 inhibitor into a pharmaceutical composition. (Id., ¶¶116–130). The composition can be prepared for oral administration. (Id., ¶¶118–123). The composition can be administered daily. (Id., ¶121). The composition can be administered in a single or multiple doses. (Id., ¶117). The composition can include the PDE9 inhibitor at a dosage in the range of about 0.0001 to about 100 mg/kg body weight per day. (Id., ¶¶121–123). Svenstrup teaches PDE9 inhibitors were known in the prior art as having been useful to treat cardiovascular disorders. (Id., ¶4) (citing Deninno).
Lee discloses PDE9 is expressed in the human heart and is upregulated by hypertrophy and cardiac failure. (Lee, p.472). Lee notes: “Increased PDE9A protein expression and cGMP-esterase activity is found in left ventricular myocardium from humans with heart failure . . . and most notably heart failure with preserved ejection fraction.” (Id., p.473). Lee discloses the potential for combination therapy with PDE9 inhibitors and angiotensin receptor blockers for treating heart conditions like heart failure:
The observation of heightened PDE9A expression in human heart failure, particularly HFPEF is exciting. Morbidity and mortality from HFPEF is high and with still no effective therapies this remains a major unmet medical need worldwide. While there is considerable enthusiasm for cGMP-PKG-targeted treatment for this disease, recent data from a multicentre clinical trial using PDE5A-I was disappointing. Among potential reasons are a lack of PDE5A upregulation and low myocardial cGMP attributed to depressed nitric oxide signalling. Our results suggest PDE9A-I as an attractive alternative. The recent success of a combined angiotensin receptor blocker and neprilysin inhibitor (the latter blunting natriuretic peptide proteolysis) that is being tested in HFPEF (NCT01920711), and advances in synthetic natriuretic peptide therapies offer opportunities for combined treatment. PDE9A inhibitors appear well tolerated inhumans and are being studied for neurocognitive disease (https://clinicaltrials.gov/ct2/show/NCT00930059). The current results support exploring these agents as new avenues for treatment of the heart, and potentially other organs in which PDE9A and the natriuretic peptide signalling system have a role.
(Id., pp.475–476).
Deninno discloses PDE9 inhibitors for the treatment of cardiovascular disorders, including congestive heart failure and related diseases that can be caused by diabetes. (Deninno, Abstract, pp.1–2). Deninno discloses the PDE9 inhibitor can be co-administered with another active agent to treat. (Id., pp.19–22). In particular, Deninno states the PDE9 inhibitor may be combined with an agent that inhibits angiotensin-converting enzyme (ACE), such as captopril, lisinopril, etc., or an angiotensin II receptor blocker, such as valsartan. (Id., p.21). Deninno states the combination of active agents “may be administered simultaneously, separately, or sequentially.” (Id., p.22).
NCT00930059 is a clinical trial of compound PF-0447943 for patients with Alzheimer’s disease. PF-0447943 is Compound 1 in the instant claims. During the trial, PF-0447943 was administered as a 25 mg tablet every 12 hours for 12 weeks.
NCT0340112 is a clinical trial of compound IMR-687 for patients with sickle cell anemia. IMR-687 is Compound 1 in the instant claims. During the trial, IMR-687 was orally administered once daily for multiple weeks. (NCT0340112, p.8).
Ascertaining the differences between the prior art and the claims at issue
Svenstrup does not disclose administering Compound 1 to treat cardiac failure in particular. Svenstrup does not disclose the specific dosage of about 20mg or 50mg. Svenstrup does not disclose administering the PDE9 inhibitor for at least 7 days. Svenstrup does not disclose administering the PDE9 inhibitor in combination with the specifically claimed agents. Lee, Deninno, NCT00930059, and NCT0340112 are relied for the disclosure of those features.
Resolving the level of ordinary skill in the pertinent art
The level of one of ordinary skill may be found by inquiring into: (i) the type of problems encountered in the art; (ii) prior art solutions to those problems; (iii) the rapidity with which innovations are made; (iv) the sophistication of the technology; and (v) the education level of active workers in the field. Custom Accessories, Inc. v. Jeffrey-Allan Industries, Inc., 807 F.2d 855, 962 (Fed. Cir. 1986). All of the factors may not be present in every case, and one or more of them may predominate. Envtl. Designs, Ltd. v. Union Oil Co., 713 F.2d 693, 696 (Fed. Cir. 1983). Based on the typically high education level of workers in the pharmaceutical art and the high degree of sophistication required to solve problems encountered in the art, Examiner finds a person having ordinary skill in the art would have at least a college degree in chemistry, biology, biochemistry, pharmacology, or a related field, and several years of experience.
Considering objective evidence present in the application indicating obviousness or nonobviousness
The data presented in the figures and referenced in the Specification (¶¶14–25; 134–166) shows Compound 1 can decrease heart size and cardiomyocyte hypertrophy. The data further shows a combination of Compound 1 and angiotensin II or nephrectomy-aldosterone decrease ANP and BNP markers, decrease cGMP levels, PKG activity, and/or decreases heart fibrosis.
The question of obviousness
Based on the above factors, it would have been prima facie obvious for a person having ordinary skill in the art, prior to the filing of the instant application, to combine the teachings of Svenstrup, Lee, Deninno, NCT00930059, and NCT0340112 to arrive at the claimed method of administering Compound 1 to a subject to treat cardiac failure. Compound 1 and its use for the treatment of cardiovascular disorders existed prior to the filing of the instant application, as noted in Svenstrup. Lee establishes a correlation between PDE9 inhibitors and cardiac failure. Lee shows it was known to administer PDE9 inhibitors with an additional therapeutic agent for the treatment of heart conditions. Deninno discloses a combination therapy comprising a PDE9 inhibitor and an angiotensin-converting enzyme (ACE) inhibitor, such as captopril and lisinopril. NCT00930059 discloses the use of Compound 1 at a single dose of about 20mg (25mg) and a twice-daily dose of about 50mg. NCT00930059 and NCT0340112 disclose orally administering Compound 1 for at least 7 days. The cited references therefore disclose each of the claim elements.
One of ordinary skill in the art would have been motivated to modify Svenstrup in view of the other references because those reference disclose the dose, dosing schedule, and/or a combination therapy can improve the treatment. There would have been a reasonable expectation of success at arriving at the claimed invention because the cited references are related to treating cardiac failure and the person having high level of skill in the art would have been capable of modifying the method in Svenstrup to improve patient outcome or to optimize the dose and dosage schedule of the co-administered active agents.
The data presented in the figures and referenced in the Specification has been considered, but the evidence does not establish an unexpected result in view of the cited references, which disclose the use of Compound 1 in clinical trials and separately suggest its use in the treatment of cardiac failure, alone or with additional therapeutic agents.
Response to Arguments
Applicant’s arguments submitted with the Reply have been fully considered but are not persuasive. Applicant states the Office Action acknowledged the combination of cited references fails to teach a method of treating cardiac failure with Compound 1. (Remarks, p.9). This is an incorrect summary of the Office Action, in which claim 2 was rejected as obvious over the cited references. Applicant next argues the cited references do not disclose the claimed dosages of about 20 mg or about 50 mg. (Id.). As noted above, NCT00930059 discloses the claimed dosages for Compound 1. Applicant next argues the established correlation between PDE9 and cardiac failure would not have led one of skill in the art, with a reasonable expectation of success, to treat cardiac failure with Compound 1. (Id., pp.9–10). Mere attorney argument is not evidence and such statements are insufficient to rebut the evidence of record. Finally, Applicant argues the data in Example 6 evidences the use of Compound 1 for treating cardiac failure at doses of about 20mg and about 50mg, resulting in a 50% reduction in NT-proBNP levels. (Id.). The data does not show the use of Compound 1 alone. Rather, each use of IMR-687 was in a combination with AngII. As such, the data is not commensurate in scope with the claims. Furthermore, the data does not indicate any unexpected result with respect to dosage.
Conclusion
Applicant’s amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 C.F.R. § 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 C.F.R. § 1.17(a)) pursuant to 37 C.F.R. § 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.
Communication
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Jason Nolan at (571) 272-2480. The examiner can normally be reached Monday through Friday between 9:00–5:00.
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/J.M.N./Patent Examiner, Art Unit 1623
/ADAM C MILLIGAN/Supervisory Patent Examiner, Art Unit 1623
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