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 .
Status of Claims
Claims 1-15 are pending.
Priority
The instant application claims priority as follows:
PNG
media_image1.png
145
584
media_image1.png
Greyscale
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Information Disclosure Statement
All references from the IDS(s) received on 11 June 2024 have been considered unless marked with a strikethrough.
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 9 is rejected under 35 U.S.C. 112(d) as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claim 1, upon which claim 9 depends, is drawn to a method for the treatment or prevention of human diseases caused by cerebral ischemia, comprising administering an effective dosage a compound of formula (I).
Here, in claim 9, how the compound is synthesized is immaterial to practicing the claimed invention. As such, the recitation that the compound “is synthesized via cyclization of 4-[2-ethoxy-5-(cis-3,5--dimethylpiperazine-1-sulfonyl) benzamide]-1-methyl-3-n-propylpyrazole-5-formamide, wherein the base catalyst is sodium tert-butoxide” is not afforded any patentable weight. Absent the recitation being afforded any patentable weight, claim 9 does not further limit claim 1.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Applicant may wish to consider whether the application provides sufficient support for a claim drawn to a method for making a compound of formula (I). However, should applicant proceed to add such a claim, the claim would be restricted as being directed to an invention that is independent or distinct from the invention originally claimed. Accordingly, such an added claim would be withdrawn from consideration as being directed to a non-elected invention. See 37 CFR 1.142(b) and MPEP § 821.03.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The framework for the objective analysis for determining obviousness under 35 U.S.C. 103 is stated in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966). Obviousness is a question of law based on underlying factual inquiries. The factual inquiries enunciated by the Supreme Court in Graham are summarized as follows:
(A) Determining the scope and content of the prior art;
(B) Ascertaining the differences between the claimed invention and the prior art; and
(C) Resolving the level of ordinary skill in the pertinent art.
Objective evidence relevant to the issue of obviousness must be evaluated by Office personnel. Id. at 17-18, 148 USPQ at 467. The evidence may be included in the specification as filed, accompany the application on filing, or be provided in a timely manner at some other point during the prosecution. The weight to be given any objective evidence is determined on a case-by-case basis. The mere fact that an applicant has presented evidence does not mean that the evidence is dispositive of the issue of obviousness.
The Supreme Court in KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395-97 (2007) identified a number of rationales to support a conclusion of obviousness which are consistent with the proper "functional approach" to the determination of obviousness as laid down in Graham. See MPEP 2143.
Examples of rationales that may support a conclusion of obviousness include:
(A) Combining prior art elements according to known methods to yield predictable results;
(B) Simple substitution of one known element for another to obtain predictable results;
(C) Use of known technique to improve similar devices (methods, or products) in the same way;
(D) Applying a known technique to a known device (method, or product) ready for improvement to yield predictable results;
(E) "Obvious to try" – choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success;
(F) Known work in one field of endeavor may prompt variations of it for use in either the same field or a different one based on design incentives or other market forces if the variations are predictable to one of ordinary skill in the art;
(G) Some teaching, suggestion, or motivation (TSM) in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-15 are rejected under 35 U.S.C. 103 as being unpatentable over Zinni et al. in view of the combined teaching Cui et al., Gratz et al., Barbas et al., Chen, Younes et al. and Muirhead et al.
Brief Discussion of the Cited References
Zinni et al. (Cells 2021, 10, 2766) teach that sildenafil is a highly potent selective phosphodiesterase type 5 (PDE-5) inhibitor and is currently approved by the FDA. Zinni et al. teaches that sildenafil is of use for the treatment of brain diseases characterized by alterations of Cerebral Blood Flow (CBF). See page 3. Zinni et al. reviews evidence supporting the neuroprotective action of sildenafil and discusses the possible benefits of the association of sildenafil with current therapeutic strategies. Zinni et al. review ongoing or completed clinical trials testing sildenafil to prevent brain injury, including trial investigating administering sildenafil to patients suffering from ischemic stroke. See Table 2. Zinni et al. state that: “The studies discussed in this review strongly suggest a neuroprotective role for sildenafil. Originally conceived as a PDE5 inhibitor for the treatment of cardiac and pulmonary dysfunction, sildenafil can modulate the complex and multiple pathogenic processes underlying the damage induced by stroke, HIE, and TBI brain injury.” See page10.
Cui et al. (Transl Androl Urol 2021;10(8):3358-3367) reiterate that “orally-administrated phosphodiesterase type 5 (PDE5) inhibitors are commonly used for treating erectile dysfunction (ED), mainly sildenafil, vardenafil, and tadalafil.” See page 3359, first column. Cui et al. teach that aildenafil citrate has been developed independently as a novel and potent PDE5 inhibitor in China for the treatment of ED. See page 3359, first column. Cui et al. investigated and reported administering aildenafil (60 mg) to men. See page 3366, first column.
Gratz et al. (Journal of Pharmaceutical and Biomedical Analysis 50 (2009) 228-231), while focusing on yet another a phosphodiesterase type 5 (PDE-5) inhibitor, namely sulfoaildenafil, teach that “[n]umerous analogs of sildenafil, tadalafil and vardenafil have been reported in the literature. In general, analogs of sildenafil, such as homosildenafil, hydroxyhomosildenafil and aildenafil (dimethylsildenafil, methisosildenafil), incorporate structural changes in the piperazine portion of the molecule.” See page 228, second column. Gratz et al. compare the structures of sildenafil and aildenafil in Fig. 2, a portion of which is reproduced below:
PNG
media_image2.png
776
702
media_image2.png
Greyscale
Barbas et al. (Cryst. Growth Des. 2018, 18, 7618-7627) teach twenty-three new solid forms of sildenafil and report that the dissolution data have been measured for some of the solid forms and that the new tartrate salt may be a potential alternative to the marketed citrate salt. See page 7694, second column.
Chen (CN 103417543 A; cited on the IDS filed 11 June 2024) teach, in claim 2, an aildenafil salt which “comprises citrate, malate, oxalates, tartrate, lactate, phosphate, pyruvate, acetate, fumarate, succinate, maleate, benzene sulfonate, oxaloacetate, hydrochlorate, sulfate, nitrate or sulphite.” Translated from Chinese with emphasis added.
Younes et al. (EFSA Journal 2020;18(3):6030) review the safety of tartaric acid isomers.
Muirhead et al. the human pharmacokinetics and metabolism of oral and intravenous dosing of sildenafil citrate.
The Claimed Invention and the Prior Art
With respect to claims 1 and 2, Zinni et al. teach that sildenafil is under active investigation as a treatment for patients suffering from ischemic stroke. Each of Zinni et al., Cui et al., and Gratz et al. teach that sildenafil is a selective phosphodiesterase type 5 (PDE-5) inhibitor. Cui et al. and Gratz et al. teach that aildenafil is also a selective PDE-5 inhibitor. Moreover, Gratz et al. compare the structure of sildenafil and aildenafil, noting that the differences reside in the piperazine portion of the molecules.
With respect to claims 3 and 5, each of Zinni et al. and Cui et al. teach citrate salts in oral dosage forms.
With respect to claims 4 and 7, Barbas et al. teach twenty-three new solid forms of sildenafil and report that the dissolution data have been measured for some of the solid forms suggesting the new tartrate salt as a potential alternative to the marketed citrate salt. See page 7694, second column. Moreover, Chen teaches aildenafil tartrate. See Chen at claim 2.
With respect to claims 6 and 13, Cui et al. teach administering aildenafil within the claimed dose ranges.
With respect to claims 8, 11 and 15, Younes et al. review the safety of isomers of tartaric acid.
With respect to claims 9, as discussed above in the rejection made under 35 USC
§ 112(d), how the compound is synthesized is immaterial to practicing the claimed invention. As such, the recitation that the compound “is synthesized via cyclization of 4-[2-ethoxy-5-(cis-3,5--dimethylpiperazine-1-sulfonyl) benzamide]-1-methyl-3-n-propylpyrazole-5-formamide, wherein the base catalyst is sodium tert-butoxide” is not afforded any patentable weight.
With respect to claim 10, each of Zinni et al. and Cui et al. teach citrate salts.
With respect to claim 12, each of Zinni et al. and Cui et al. teach one or more of the claimed dosage forms.
With respect to claim 14, Muirhead et al. teach the human pharmacokinetics and metabolism of oral and intravenous dosing of sildenafil citrate. Moreover, Cui et al. teach administering aildenafil citrate orally within the claimed dose ranges.
Differences between the Claimed Invention and the Prior Art
With respect to claims 1-3, 5, 6, 9, 10, 12 and 13, although Zinni et al. teach using sildenafil in methods for the treatment or prevention of human diseases caused by cerebral ischemia, no cited reference expressly teaches using aildenafil in methods for the treatment or prevention of human diseases caused by cerebral ischemia.
With respect to claims 4, 7, 8, 11 and 15, no cited reference expressly teaches methods using an L(+)-tartrate salt of aildenafil for the treatment or prevention of human diseases caused by cerebral ischemia.
With respect to claims 14, no cited reference expressly teaches methods using an injectable formulation of aildenafil for the treatment or prevention of human diseases caused by cerebral ischemia.
Conclusion of Obviousness
With respect to claims 1-3, 5, 6, 9, 10, 12 and 13, applying KSR rationale (B) outlined above, it would have been prima facie obvious to substitute one known element (namely, aildenafil taught by Cui et al.) in place of another known element (namely, sildenafil taught by Zinni et al.) to obtain the claimed methods for the treatment or prevention of human diseases caused by cerebral ischemia, including ischemic cerebral stroke and traumatic brain injury. Owing to the striking similarities between the structures of sildenafil and aildenafil, and that the sildenafil and aildenafil are both selective phosphodiesterase type 5 (PDE-5) inhibitors, one of ordinary skill in the art would have had a reasonable expectation that substituting aildenafil in place of sildenafil would offer outcomes similar to those as expected for sildenafil. As such, the claimed invention was obvious at the time of filing.
With respect to claims 4, 7, 8, 11 and 15, applying KSR rationale (B) outlined above, would have been prima facie obvious to substitute one known element (namely, aildenafil tartrate taught by Chen) in place of another known element (namely, aildenafil citrate taught by Cui et al.) to obtain the claimed methods using aildenafil tartrate for the treatment or prevention of human diseases caused by cerebral ischemia. Regarding the selection of a particular isomer or tartrate, one of ordinary skill would have been motivated to select an isomer suitable for the specifics needs of the situation, and a preference would have been given to L(+)-tartaric acid in view of its increased safety profile, as discussed by Younes et al. As such, the claimed invention was obvious at the time of filing.
With respect to claim 14, applying KSR rationale (B) outlined above, it would have been prima facie obvious to substitute one known element (namely, injectable formulations taught Muirhead et al.) in place of another known element (namely, an oral formulations taught by Cui et al.) to obtain the claimed methods using an injectable formulation for the treatment or prevention of human diseases caused by cerebral ischemia. Muirhead et al. teach that intravenous dosing of sildenafil citrate resulted in decreased first-pass metabolism compared to oral dosing. Owing to the striking similarities between the structures of sildenafil and aildenafil, one of ordinary skill would have had a reasonable expectation that an intravenous dosing of aildenafil would result in decreased first-pass metabolism compared to oral dosing. Moreover, one of ordinary skill would have been motivated to select a dosage form (whether oral or injectable) suitable for the specifics needs of the situation. For example, one of ordinary skill would have selected an oral dosage form for its convenience or selected an injectable form where the patient could not swallow. As such, the claimed invention was obvious at the time of filing.
Conclusion
No claim is currently allowable.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to BRADLEY S MAYHEW whose telephone number is
571-272-8428. The examiner can normally be reached Mon-Fri, 11:00 AM-7:00 PM.
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, CLINTON A BROOKS can be reached at 571-270-7682. 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.
/BSM/Examiner, Art Unit 1621
/CLINTON A BROOKS/Supervisory Patent Examiner, Art Unit 1621
Prosecution Insights