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
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 12/02/2025 has been entered.
Response to Amendment
Acknowledgment is made of the receipt and entry of the amendment filed on 12/02/2025.
Status of Claims
Claims 66, 68-69, and 78-80 are pending and under examination in the instant application.
Action Summary/ Response to Arguments
Applicant’s Remarks filed 12/02/2025 have been fully considered, but are NOT persuasive to overcome rejections anticipated by Black under 35 USC § 102, and over Black in view of Lee and Kim under 35 USC § 103 on the record.
35 USC § 112 rejection
Claims 66, 68-69, and 78-80 are rejected under 35 USC § 112(a) for scope of enablement. The PDE9 inhibitors disclosed by instant specification (See [0079] [0080]) are incorporated from WO03/037899, WO03/037432, and U.S. patent application No.10 / 828,485 for treating type 2 diabetes, metabolic syndrome, and cardiovascular disease. However, instant specification does not sufficiently describe these vast variety of PDE9 inhibitors as treating “obesity in a subject in which a nitric oxide (NO) pathway is compromised”. Obesity is associated with variety of disease/disorder and metabolic pathway. Due to the high unpredictability of treating obesity and lack of sufficient support by instant specification, an ordinary skilled in the art would not know whether instantly claimed vast variety of PDE 9 inhibitors would be enabled for the method of treating “obesity in a subject in which a nitric oxide (NO) pathway is compromised”.
35 USC § 102 rejection anticipated by Black
Applicant argues "[a] claim is anticipated only if each and every element as set forth in the claim is found, either expressly or inherently described, in a single prior art reference." Verdegaal Bros. v. Union Oil Co. of California, 814 F.2d 628, 631, 2 USPQ2d 1051, 1053 (Fed. Cir. 1987)”.
RESPONSE: Applicant’s argument is fully considered, but not persuasive.
As stated in MPEP 2131.01, III Extra Reference or Evidence Can Be Used To Show an Inherent Characteristic of the Thing Taught by the Primary Reference, "To serve as an anticipation when the reference is silent about the asserted inherent characteristic, such gap in the reference may be filled with recourse to extrinsic evidence. Such evidence must make clear that the missing descriptive matter is necessarily present in the thing described in the reference, and that it would be so recognized by persons of ordinary skill." Continental Can Co. USA v. Monsanto Co., 948 F.2d 1264, 1268, 20 USPQ2d 1746, 1749-50 (Fed. Cir. 1991).
In instant case, Black explicitly teaches a method of treating obesity/reducing body weight/body fat in obese/overweight patients in need thereof by administering a PDE9 inhibitor recited in instant claim 66, 3-isopropyl-5-[2-(2-morpholin-4-yl-ethoxy)-benzyl]-1,6-dihydro-pyrazolo[4,3-d] pyrimidin-7-one (Compound A) . Black explicitly teaches decrease in PDE9 activity is an effective way to treat animal patients that are overweight, obese (See page 12, lines 18-30). Although Black is silent about the subject has a comprised nitric oxide (NO) pathway or has an estrogen deficiency due to menopause or oophorectomy. As explained in last office action, “the patients in need thereof” taught by Black is construed as encompassing all subjects in need of decreasing body weight/body fat, including subject having compromised nitric oxide (NO) pathway, or estrogen deficiency due to menopause or oophorectomy though Black might not be aware of it. Further, biological activity of PDE-9 inhibitor is inherent property of PDE9 inhibitor. As evidenced by Lee, phosphodiesterase 9A controls nitric-oxide independent cGMP and PDE 9 inhibitor could provide an effective treatment in subjects with nitric oxide signaling deficiency.
Please note 3-isopropyl-5-[2-(2-morpholin-4-yl-ethoxy)-benzyl]-1,6-dihydro-pyrazolo[4,3-d] pyrimidin-7-one (Compound A) is one of the non-elected PDE9 inhibitor species as recited in instant claim 66. If instantly claimed PDE9 inhibitors are effective in treating obesity in subjects with compromised NO pathway as alleged, Compound A taught by Black would have been working as instant claims alleged. The Office does not have the facility to verify whether Black’s method of treating obesity would work in a subject in need thereof or NOT. The burden is shifted to the Applicant to provide evidence the PDE 9 inhibitors taught by Black, e.g. 3-isopropyl-5-[2-(2-morpholin-4-yl-ethoxy)-benzyl]-1,6-dihydro-pyrazolo[4,3-d] pyrimidin-7-one (Compound A) would NOT treat obesity in a subject which nitric oxide pathway is compromised.
35 USC § 103 rejection
Applicant argues “to establish prima facie obviousness of a claimed invention, all the claim features must be taught or suggested by the prior art. In re Royka, 490 F.2d 981, 180 USPQ 580 (CCPA 1974). Black is silent about the subject has a comprised nitric oxide (NO) pathway or has an estrogen deficiency due to menopause or oophorectomy and Lee is silent with regard to the use of PDE9 inhibitors for treating obesity. Kim is silent with regard to treating obesity” .
RESPSONSE:
In response to applicant's arguments against the references individually, one cannot show non-obviousness 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). The test for obviousness is not that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art.
Black explicitly teaches a method of treating obesity/reducing body weight in need thereof by administering a PDE9 inhibitor recited in instant claim 66, 3-isopropyl-5-[2-(2-morpholin-4-yl-ethoxy)-benzyl]-1,6-dihydro-pyrazolo[4,3-d] pyrimidin-7-one (Compound A). Lee (2015) by instant co-inventor teaches phosphodiesterase 9A controls nitric-oxide independent cGMP and hypertrophic heart disease, and explicitly teaches “PDE9A-I as an alternative, unlike PDE5A-I, remains effective even when NOS-dependent cGMP synthesis is suppressed”, indicating PDE 9 inhibitor (e.g. PF-04447943) could provide an effective treatment in subjects with nitric oxide signaling deficiency. Based on Lee reference, Kim reference (2017) by instant co-author Dr. Kass further teaches heart failure with preserved ejection fraction (HFpEF) particularly affects older women and reduced NO-signaling consequent to menopause , and explicitly teaches targeting PDE9A inhibition may circumvent obstacles posed by depressed NO-dependent signaling. Obesity is closely related to heart disease. It would be prima facie obvious for skilled artisan to combine these teaching together with general knowledge of treating obesity and related disease/condition (e.g. cardiac disease) and reasonably arrive at instantly claimed method of treating obesity in a subject with compromised NO pathway by administering a PDE 9 inhibitor.
As acknowledged by instant specification(See [0007]), Lee (2015) provides evidence that “ PDE9 does not regulate cGMP generated by the NO-GO-1 or NO- GC- 2 signaling pathway, but hydrolyzes cGMP generated by the GC-A and GC-B pathway. This is very important , since it meant that the efficacy of PDE9 inhibitors to treat heart disease was not diminished by conditions that blunt nitric oxide synthesis”. If instantly claimed PDE9 inhibitors are effective in treating obesity in subjects with compromised NO pathway as alleged, it only further validate Lee’s teaching of PDE 9 on nitric oxide pathway.
In response to applicant’s argument that there is no teaching, suggestion, or motivation to combine the references, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988). In this case, all reference are directed to PDE9 inhibitors. Black explicitly teaches PDE9 inhibitors could be used for treating obesity. Both Lee and Kim teach PDE 9 inhibitor (e.g. PF-04447943) remain effective in treating disease associated with cGMP (e.g. heart disease) even when NOS-dependent cGMP synthesis is suppressed. Kim teaches estrogen deficiency due to menopause or ovariectomy relates with reduced NO-signaling and explicitly teaches targeting PDE9A inhibition may circumvent obstacles posed by depressed NO-dependent signaling. Obesity is closely related with heart disease. A skilled artisan would be motivated to combine the teachings of Lee and Kim for treating subjects with depressed NOS-dependent cGMP synthesis, e.g. obese subjects and reasonably expect PF-04447943 to be effective in treating obese subjects with depressed NO pathway.
Priority
The instant application 17/283,217 filed on 04/06/2021 is a 371 of PCT/US2019/055096 filed 10/08/2019 which claims benefit of US provisional applications 62/742,674 filed 10/08/2018.
Claim Rejections - 35 USC § 112
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.
Scope of enablement rejection
Claims 66, 68-69, and 78-80 are rejected under 35 U.S.C. 112(a) first paragraph, as failing to comply with the enablement requirement. The claims contain subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to practice the invention commensurate in scope with these claims. The specification, while be enabling for a method of treating obesity in a subject which a nitric oxide (NO) pathway is compromised, by administering specific PDE9 inhibitor (e.g. PF-04447943 ) to the subject , does not reasonably provide enablement for vast variety of PDE 9 inhibitors genus as recited in claim 66. This is a scope of enablement rejection.
To be enabling, the specification must teach those skilled in the art how to make and use the full scope of the claimed invention without undue experimentation. In re Wright, 999 F.2d 1557, 1561 (Fed. Cir. 1993). The determination that "undue experimentation" would have been needed to practice the claimed invention in full scope is not a single, simple factual determination.
As stated in the MPEP 2164.01(a), “There are many factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is "undue." In In re Wands, 8 USPQ2d 1400 (1988), factors to be considered in determining whether a disclosure meets the enablement requirement of 35 U.S.C. 112, first paragraph, have need described. They are:
(A) The breadth of the claims;
(B) The nature of the invention;
(C) The state of the prior art;
(D) The level of one of ordinary skill;
(E) The level of predictability in the art;
(F) The amount of direction provided by the inventor;
(G) The existence of working examples; and
(H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
These factors are always applied against the background understanding that scope of enablement varies inversely with the degree of unpredictability involved. Keeping that in mind, the Wands factors are relevant to the instant application for the following reasons:
The Breadth of The Claims/ Nature of The Invention
Instant claims are directed to a method for treating obesity in a subject in which a nitric oxide (NO) pathway is compromised and claim 66 recites vast variety of PDE9 inhibitors that have different structures, different chemical and physical properties, different pharmacological activities and efficacies.
The State of the Prior Art and the Predictability or Lack Thereof in the Art
It’s well known that obesity treatment is challenging due to multiple factors and obesity is associated with variety of disease/disorder involving variety of metabolic pathways. Sansbury (2014) teaches variety of metabolic pathways known to regulate obesity, e.g. nitric oxide (See page 4-7) wherein nitric oxide bioavailability is decreased in animal models of diet-induced obesity and in obese and insulin resistant patients, and increasing NO output has remarkable effects on obesity and insulin resistance. With regard to nitric oxide signaling regulated by PDE inhibitor. as disclosed by Lee, the effect of PDE inhibitors regulates nitric-oxide-stimulated cGMP differently, e.g. PDE9A inhibition reverses pre-established heart disease independent of nitric oxide synthase (NOS) activity, whereas PDE5A inhibition requires active NOS. As such, treatment of obesity and heart disease ( e.g. heart failure with a preserved ejection fraction (HFpEF) with PDE inhibitors targeting at nitric oxide pathway are highly unpredictable.
More generally, the invention is directed toward medicine and is therefore physiological in nature. It is well established that “the scope of enablement varies inversely with the degree of unpredictability of the factors involved,” and physiological activity (e.g., cancer prevention) is generally considered an unpredictable factor. See In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970).
The Amount of Direction Present and Presence or Absence of Working Examples
The specification does not provide sufficient working examples for a skilled artisan to practice the claimed method of treating obesity in a subject in which a nitric oxide (NO) pathway is compromised in its full scope.
Instant specification only disclosed assay and results thereof with PF-04447943, a small molecule PDE9 inhibitor (See [0129], Figure 1). Instant specification does not disclose assay with other structurally different small molecule PDE9 inhibitor(s). Instant specification does not provide sufficient description of representative species to reflect the vast variation of PDE inhibitors. Instant application does not sufficiently describe the invention as it relates to treating “obesity in a subject in which a nitric oxide (NO) pathway is compromised” with vast variety of PDE9 inhibitors.
The level of one of ordinary skill in the art
The level of skill required to make and/or use the instant invention would likely require many years of professional experience conducting research in the art (e.g., medicine, pharmaceutical science, biology, biochemistry, medicinal chemistry, and/or organic chemistry, etc.) as well as an advanced educational degree (e.g., M.D. and/or Ph.D.) commensurate in level with the advanced techniques involved in the preparation and/or use of the instant invention.
The quantity of experimentation needed
It would be a great burden for one of ordinary skill in the art to carry out undue experimentation to use the claimed invention in full scope. An unduly extensive amount of experimentation would be required for one of ordinary skill in the art to develop protocols for vast variety of PDE9 inhibitors that have different structures, different chemical and physical properties, different pharmacological activities/efficacies, etc. Working examples would be needed to determine the therapeutically effective dose for different PDE9 inhibitor. The therapeutically effective amount may vary depending on many factors, such the physical properties, pharmacological activities, pharmacokinetic profile of the inhibitor, the subject, the disease condition and intended treatment outcome, etc.
Conclusion
MPEP 2164.01(a) states, “A conclusion of lack of enablement means that, based on the evidence regarding each of the above factors, the specification, at the time the application was filed, would not have taught one skilled in the art how to make and/or use the full scope of the claimed invention without undue experimentation. In re Wright, 999 F.2d 1557,1562,27 USPQ2d 1510, 1513 (Fed. Cir. 1993).” That conclusion is clearly justified here with respect to the claimed method in view of the analysis above pursuant to In re Wands. In other words, one skilled in the art could not practice the claimed invention without undue experimentation.
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 66, 68-69 and 78-79 are rejected under 35 U.S.C. 102(a)(1) and (a) (2) as being anticipated by Black et al. (WO 2005/041972 A1, Applicant’s IDS dated 01/04/2022), as evidenced by LEE et al.( Nature, 2015 Mar 26;519(7544):472-6, Applicant’s IDS dated 01/04/2022, “Phosphodiesterase 9A controls nitric-oxide-independent cGMP and hypertrophic heart disease”).
Black disclosed a method of treating obesity/reducing body weight/body fat in obese/overweight patients in need thereof by administering a PDE9 inhibitor(See abstract; page 4, lines 6-10; claims 1-4). Black teaches cyclic nucleotide phosphodiesterases PDEs play a pivotal regulatory role in a wide variety of signal transduction pathways(See page 2, lines 1-34).
Regarding the PDE-9 inhibitor for treating obesity recited in claim 66, Black and its incorporated reference teach a variety of PDE9 inhibitors, e.g. 3-isopropyl-5-[2-(2-morpholin-4-yl-ethoxy)-benzyl]-1,6-dihydro-pyrazolo[4,3-d] pyrimidin-7-one (Compound A) (See pages 13-14, lines 1-34 ). Please refer to Black for list of PDE-9 inhibitor that read on instant claim 66.
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Black explicitly teaches the activity of Compound A on body weight/body fat which shows a reduced body weight gain in ob mice as compared to the mice fed with control (See abstract; page 43, lines 15-30; Fig. 7 and Fig. 8A). Black teaches Compound A also decreased glucose, triglycerides and fructosamine (See page 43, lines 24-26, Fig. 10-12). Black concludes decreasing PDE9 activity is an effective method to reduce body weight and/or body fat for treating obesity (See page 43, lines 27-30).
Regarding the male and female subject limitation of instant claims 68 and 69, Black teaches effect of PDE9 gene disruption on body weight, body composition, and metabolites on male and female mice (See page 39, lines 24-34; page 42, lines 1-10). Black further teaches the plasma metabolites following the high fat diet wherein female KO mice demonstrated increased cGMP, decreased glucose, and decreased insulin (page 42, See Table 1).
Black is silent about the subject has a comprised nitric oxide (NO) pathway or has an estrogen deficiency due to menopause or oophorectomy. Please note “the patients in need thereof” taught by Black is construed as encompassing all subjects in need of decreasing body weight/body fat, including subject having compromised nitric oxide (NO) pathway, or estrogen deficiency due to menopause or oophorectomy though Black might not be aware of it. One of ordinary skilled in the art would expect administering a PDE9 inhibitor provide a treatment for obesity in subjects in need thereof as taught by Black whether the subject has compromised nitric oxide (NO) pathway, or estrogen deficiency due to menopause or oophorectomy, in absence of evidence to the contrary.
More importantly, biological activity of PDE-9 inhibitor is inherent property of PDE9 inhibitor. As evidenced by Lee, phosphodiesterase 9A controls nitric-oxide independent cGMP and PDE 9 inhibitor could provide an effective treatment in subjects with nitric oxide signaling deficiency.
Applicant might have discovered a new pathway/ mechanism or benefit of PDE-9 inhibitor for treating obesity in a patient in need thereof which was already taught by the prior art. MPEP 2112 I states: “[T]he discovery of a previously unappreciated property of a prior art composition, or of a scientific explanation for the prior art’s functioning, does not render the old composition patentably new to the discoverer.” Atlas Powder Co. v. Ireco Inc., 190 F.3d 1342, 1347, 51 USPQ2d 1943, 1947 (Fed. Cir. 1999). Thus, the claiming of a new use, new function or unknown property which is inherently present in the prior art does not necessarily make the claim patentable. In re Best, 562 F.2d 1252, 1254, 195 USPQ 430, 433 (CCPA 1977).” Instant claims do not recite any administration regimen (e.g. dose, route, etc.) that are different from Black. Thus, Black anticipates instant claimed invention.
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 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.
Claims 66, 68-69, and 78-80 are rejected under 35 USC § 103 as being unpatentable over Black et al. (WO 2005/041972 A1, Applicant’s IDS dated 01/04/2022), as applied to 35 USC § 102 rejection above, and further in view of LEE et al.( Nature, 2015 Mar 26;519(7544):472-6, Applicant’s IDS dated 01/04/2022, “Phosphodiesterase 9A controls nitric-oxide-independent cGMP and hypertrophic heart disease”) and KIM et al.( Handb Exp Pharmacol 2017: 243, pp 249-269, Applicant’s IDS dated 01/04/2022, “Cardiac Phosphodiesterase and Their Modulation for Treating Heart Disease”).
The collective teachings of Black are elaborated in preceding 102 rejection and applied as before. Black teaches a method of treating obesity in patients in need thereof by administering a PDE9 inhibitor (e.g. compound A) to the subject. Please note “the patients in need thereof” taught by Black is construed as encompassing all subjects in need of decreasing body weight/body fat, including the subject having compromised nitric oxide (NO) pathway.
Black is silent about the elected species, PF-04447943.
Lee and its incorporated references (Verhoest,2012, etc. ) teaches PF-04447943 is a selective PDE9 inhibitor used in clinical trial for treating a variety of disease (e.g. heart disease, etc.)(See page 3, first paragraph; page 6, second paragraph, Fig. 3). Lee teaches PDE9A selectivity over PDE 5A: “PDE9A inhibition reverses pre-established heart disease independent of nitric oxide synthase (NOS) activity, whereas PDE5A inhibition requires active NOS. Transcription factor activation and phosphoproteome analyses of myocytes with each PDE selectively inhibited reveals substantial differential targeting, with phosphorylation changes from PDE5A inhibition being more sensitive to NOS activation. Thus, unlike PDE5A, PDE9A can regulate cGMP signaling independent of the nitric oxide pathway”(See Abstract). Lee teaches “PDE9A-I as an alternative that, unlike PDE5A-I, remains effective even when NOS-dependent cGMP synthesis is suppressed” (See page 4, last paragraph), indicating PDE 9 inhibitor (e.g. PF-04447943) could provide an effective treatment in subjects with nitric oxide signaling deficiency.
Regarding heart failure with a preserved ejection fraction (HFpEF) limitation recited in claim 80, Lee teaches “Increased PDE9A protein expression and cGMP-esterase activity is found in left ventricular myocardium from humans with heart failure and depressed function (Fig. 1c–e, Extended Data Fig. 2b, c and Extended Data Table 1). Protein expression also increases in human left ventricular hypertrophy from aortic stenosis (pressure overload) and most notably in heart failure with preserved ejection fraction (HFPEF, Fig. 1f)” (See page 2, third paragraph).
Black and Lee are silent about estrogen deficiency due to menopause or oophorectomy in the female subject of claims 69 and 78.
Kim teaches roles of PDEs (e.g. PDE 5 and PDE 9) and their differential control over cAMP and cGMP signaling in various cell types to explore the utility of targeted PDE inhibition for treating disease (See Abstract). Kim and its incorporated reference teach estrogen deficiency due to menopause or ovariectomy relates with reduced NO-signaling (See page 7, second paragraph): “ HFpEF particularly affects older women and reduced NO-signaling consequent to menopause maybe provide another reason for little impact from PDE5A inhibition. In women, the estrogen receptor couples to NOS-dependent cGMP synthesis via a non-transcriptional signaling pathway … As this NO-derived cGMP is the primary target of PDE5A, its decline post menopause may limit the efficacy of PDE5A inhibition … female mice with Gαq-over expression or pressure-overload induced heart disease responded favorably to PDE5A inhibition, but this benefit was lost if the mice underwent ovariectomy”.
Incorporating Lee’s teaching about PDE 9A, Kim further teaches “PDE9A is the most selective for cGMP from all the 11 species…. Importantly, PDE9A regulation of cGMP is distinct from PDE5A, in that the former selectively hydrolyzes cGMP derived from NP stimulation... These results have potentially significant therapeutic implications as NOS declines in many HF patients … compromised in women by the decline in estrogen post menopause. Targeting PDE9A inhibition may circumvent obstacles posed by depressed NO-dependent signaling” (See page 9, third paragraph, PDE9A).
It would have been prima facie obvious for one of the ordinary skilled in the art before the effective filing date of instant invention to explore the use of PF-04447943 taught by Lee for the method of treating obesity with PDE9 inhibitor taught by Black, together with the beneficial teachings of PDE9 inhibitor in subjects with depressed NO-dependent signaling as taught by Lee and Kim, and arrive at instantly claimed invention with reasonable expectation of success. At the time of the instant invention was made, it was already known that PDE9 inhibitors could be used for treating obesity. It was also known that PF-04447943 is a selective PDE 9 inhibitor that regulates cGMP signaling independent of nitric oxide pathway and is effective even when NOS-dependent cGMP synthesis is suppressed as taught by Lee. Kim teaches estrogen deficiency due to menopause or ovariectomy relates with reduced NO-signaling and explicitly teaches targeting PDE9A inhibition may circumvent obstacles posed by depressed NO-dependent signaling.
It’s commonly known that obesity is closely related with heart disease. A skilled artisan would be motivated to explore the use of PF-04447943 taught by Lee for treating obesity as taught by Black because PF-04447943 is a selective PDE 9 inhibitor and effective even in subjects with depressed NO-dependent signaling (e.g. estrogen deficiency) as taught by Lee and Kim. Kim explicitly teaches targeting PDE9A inhibition may circumvent obstacles posed by depressed NO-dependent signaling. The combined teachings of prior art, together with general knowledge of treating PDE9 associated disease would provide a novel treatment for obesity with selective PDE 9 inhibitor PF-04447943, especially for subjects with comprised nitric oxide pathways.
One of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention based on the combined teachings of prior art and general knowledge of treating PDE9 associated disease (e.g. obesity). Therefore, the invention as a whole is prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Conclusion
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/LIYUAN MOU/
Examiner, Art Unit 1628
/JARED BARSKY/Primary Examiner, Art Unit 1628