DETAILED ACTION
Claims 1-12 were pending; claim 13 was newly added per the Reply of 1/3/2026.
Claims 1-13 are pending.
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 .
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 1/3/2026 has been entered.
Priority
The instant application filed 5/13/2022 is a Continuation of PCT/KR2019/015662, filed 11/15/2019. The instant application claims foreign priority to 10-2019-0146217, filed 11/14/2019; claims foreign priority to 10-2019-0146222, filed 11/14/2019; claims foreign priority to 10-2019-0146223, filed 11/14/2019; and claims foreign priority to 10-2019-0146225, filed 11/14/2019.
Claim Rejections - 35 USC § 103
(Maintained)
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 1-9 and 11-13 are rejected under 35 U.S.C. 103 as being unpatentable over Shibuya et al. “Effects of fasudil in acute ischemic stroke: Results of a prospective placebo-controlled double-blind trial,” Journal of the Neurological Sciences 238 (2005) 31 – 39; Chen et al. “Neuroprotection by Sildenafil: Neuronal Networks Potentiation in Acute Experimental Stroke,” CNS Neuroscience & Therapeutics 20 (2014) 40–49; and Al-Mamun “Combination Therapy with a Rho-Kinase Inhibitor (Fasudil) and a PDE5 Inhibitor (Sildenafil) Ameliorates Monocrotaline-Induced Pulmonary Hypertension and Survival in Rats,” Tohoku University 2014.
Claim 1 is generally directed towards treating a patient having an ischemic stroke (brain) with fasudil and sildenafil (in combination).
Shibuya teaches treating ischemic stroke with fasudil.
Chen teaches treating ischemic stroke with sildenafil.
Al-Mamun teaches fasudil and sildenafil have synergy in their mechanism stating, “it is found that fasudil and sildenafil can synergize each other activity in terms of Rho-kinase and eNOS expression beyond their individual activities.”
One would combine the two known treatments of ischemic stroke, fasudil and sildenafil because the two drugs have been shown to have synergy in there phamacodynamic pathway in another related disease and one would expect the combination to treat the disease better than the use of the two drugs individually. As such claim 1 was prima facie obvious at the time of filing.
Instant claim 1 states a method for treating an ischemic cerebrovascular disease or sequelae following the ischemic cerebrovascular disease, the method including administering a pharmaceutical composition to an individual, wherein the pharmaceutical composition comprising a phosphodiesterase type 5 activity inhibitor; and a Rho- associated kinase (ROCK) inhibitor.
Instant claim 2 states, ischemic cerebrovascular disease includes ischemic stroke (cerebral infarction), thrombosis, embolism, transient ischemic attack, leukoplakia and small infarction.
Instant claim 3 states, wherein the sequelae following the ischemic cerebrovascular disease is any one selected from the group consisting of loss of locomotor activity, an anxiety disorder and cognitive function decline.
Shibuya teaches treating ischemic stroke with fasudil and states, “fasudil significantly improved neurological dysfunction and clinical outcome in acute cerebral thrombosis. Clinical effectiveness of fasudil in patients with acute stroke may be due to the reduction of the various secondary brain damage such as the inflammatory reactions and hemodynamic abnormalities by inhibiting Rho-kinases.”
Chen teaches treating ischemic stroke with sildenafil and states, “Ischemia leads to severe behavioral disturbance and histological changes in rats. The results of the behavioral studies showed that sildenafil-treated rats obtained higher beam walking scores and took longer to fall from a rotating rod (P < 0.05, Figure S1). Furthermore, compared with the sham-operated group, the neurological deficit, cerebral infarct volume, and cerebral edema were significantly higher in the MCAO group and could be significantly reversed by sildenafil, even after a 4-h delay in administration poststroke (P < 0.05, Figure 1).”
Both drugs improve patient outcome, as such one would reasonably expect the outcome of the combination to also improve the patient’s cognitive function as required by instant claims 8, 12, and 13. The outcome of the treatment of the disease flows naturally from the treatment. Therefore these claims directed to the outcome of the treatment don’t lend to patentability.
Looking to the MPEP 2111.04 discussing Claim Interpretation, we see this quote about interpreting Contingent Clauses (Wherein): The determination of whether each of these clauses is a limitation in a claim depends on the specific facts of the case. See, e.g., Griffin v. Bertina, 285 F.3d 1029, 1034, 62 USPQ2d 1431 (Fed. Cir. 2002) (finding that a "wherein" clause limited a process claim where the clause gave "meaning and purpose to the manipulative steps"). In In re Giannelli, 739 F.3d 1375, 1378, 109 USPQ2d 1333, 1336 (Fed. Cir. 2014), the court found that an "adapted to" clause limited a machine claim where "the written description makes clear that 'adapted to,' as used in the [patent] application, has a narrower meaning, viz., that the claimed machine is designed or constructed to be used as a rowing machine whereby a pulling force is exerted on the handles." In Hoffer v. Microsoft Corp., 405 F.3d 1326, 1329, 74 USPQ2d 1481, 1483 (Fed. Cir. 2005), the court held that when a "‘whereby’ clause states a condition that is material to patentability, it cannot be ignored in order to change the substance of the invention." Id. However, the court noted that a "‘whereby clause in a method claim is not given weight when it simply expresses the intended result of a process step positively recited.’" Id. (quoting Minton v. Nat’l Ass’n of Securities Dealers, Inc., 336 F.3d 1373, 1381, 67 USPQ2d 1614, 1620 (Fed. Cir. 2003)).
In this method, the wherein clause is simply expressing the intended result of a process step positively recited. When a patient with ischemic stroke is administered a therapeutically effective amount of fasudil and sildenafil the patients outcomes will improve, including events that are directly related to the stroke (sequelae following the ischemic cerebrovascular disease is an anxiety disorder). As such the clause does not lend to patentability.
Instant claim 4 states, wherein the phosphodiesterase type 5 activity inhibitor is any one selected from the group consisting of mirodenafil, sildenafil, vardenafil, tadalafil, udenafil, dasantafil, avanafil and pharmaceutically acceptable salts, solvates and hydrates thereof. This drug was known in the art to treat ischemic stroke, see Chen.
Instant claim 5 states, wherein the ROCK inhibitor is any one selected from the group consisting of fasudil, ripasudil, RKI-1447, Y-27632, GSK429286A, Y-30141 and pharmaceutically acceptable salts, solvates and hydrates thereof. This drug was known in the art to treat ischemic stroke, see Shibuya.
Instant claim 6 states wherein the administration before reperfusion after cerebrovascular occlusion, simultaneously with the reperfusion or after the reperfusion. Both the Shibuya and Chen references give the drugs after ischemia, however one would expect the drugs to work at any time point. As such in the absence of evidence as to the timing of treatment playing a significant role in the invention, all timing intervals would be considered obvious.
Instant claim 7 (independent) states method for improving a prognosis of an ischemic cerebrovascular disease, the method including administering a pharmaceutical composition to an individual, wherein the pharmaceutical composition comprising a phosphodiesterase type 5 activity inhibitor; and a Rho-associated kinase (ROCK) inhibitor. This claim is rendered obvious as is claim 1 using the same art and rationale. As the difference in the claims, instant claim 1 and instant claim 7 is the preamble. The scope of the patient population includes treating ischemic stroke.
Instant claim 8 (independent) states a method for enhancing a cognitive function, the method including administering a pharmaceutical composition to an individual, wherein the pharmaceutical composition comprising a phosphodiesterase type 5 activity inhibitor; and a Rho-associated kinase (ROCK) inhibitor. This claim is rendered obvious as is claim 1 using the same art and rationale. As the difference in the claims, instant claim 1 and instant claim 8 is the preamble. The scope of the patient population includes treating ischemic stroke.
Instant claim 9 requires the administration occur after reperfusion. Chen teaches 2 h after for PDE5 inhibitor, and Shibuya teaches the fasudil is given 48 hours after. Therefore after is met by the teaching.
Instant claim 11 requires intraperitoneal administration. Chen states, “followed by intraperitoneal or intravenous treatment of sildenafil starting 2 h later.” Shibuya teaches the fasudil was administered by intravenous admin. Given this, one would look to optimize dosing and in order to aid convenience one could give both drugs via either route, as the systemic exposure would occur via either method.
RESPONSE to Applicant’s Arguments: Applicant argues that the instant claims are patentable because the results are synergistic which Applicant states is “unexpected.”. However, Al-Mamun states, “It was previously demonstrated that treatment with a Rho-kinase inhibitor, fasudil, ameliorates PH in animal models. Here, I examined whether combination therapy with fasudil and sildenafil further ameliorates PH in rats.” Then Al- Mamun demonstrated synergy in the treatment of PH. This same methodology would be applied to treating ischemic stroke, and one would expect synergy. Therefore this is known in the art.
Applicant points to statements in the Specification [0132]noting: "the effects of a decrease in damage to brain tissue, amelioration of loss of locomotor activity, amelioration of an anxiety disorder or amelioration of cognitive function decline were better than by single treatment with the drug.” This is not evidence of an unexpected result. Looking to MPEP 716.02(a) Evidence Must Show Unexpected Results. In this case using 2 drugs known to treat a disease together would be expected to treat the disease in combination, in which the efficacious dose would potentially be half for each drug. Moreover, the art shows synergy in the mechanism. Therefore the art expects more that additive effects. Again, Applicant’s results are not unexpected.
Applicant points to Example 2 from the Specification, “Example 2, the specification discloses that a combination therapy of sildenafil and a ROCK inhibitor exhibit from 4.8 to 6-fold increased effect on the reduction of brain tissue damage in an ischemic stroke animal model.” This is the same animal model each drug is known to be effective in, as taught in the art. As such this is not unexpected.
Applicant argues the synergy in PH, one would not expect synergy in ischemic stroke. This is not the case, as again Al- Mamun is not only teaching synergy, but how to fine synergy in this pathway, and one would look to combine the treatments. Therefore this is not persuasive.
Lastly Applicant argue the cognitive function benefit is not taught in the art and therefore unexpected. The problem here is that individually the drugs improve cognitive function, and therefore the combination would be expected too as well. Moreover, simply reciting the outcome of the methods step does not lend to patentability. MPEP 2111.04 states, “In Hoffer v. Microsoft Corp., 405 F.3d 1326, 1329, 74 USPQ2d 1481, 1483 (Fed. Cir. 2005), the court held that when a "‘whereby’ clause states a condition that is material to patentability, it cannot be ignored in order to change the substance of the invention." Id. However, the court noted that a "‘whereby clause in a method claim is not given weight when it simply expresses the intended result of a process step positively recited.’" Id. (quoting Minton v. Nat’l Ass’n of Securities Dealers, Inc., 336 F.3d 1373, 1381, 67 USPQ2d 1614, 1620 (Fed. Cir. 2003))” Therefore this is not persuasive.
Claim Rejections - 35 USC § 103
(Maintatined Rejection)
Claims 1-13 are rejected under 35 U.S.C. 103 as being unpatentable over Shibuya et al. “Effects of fasudil in acute ischemic stroke: Results of a prospective placebo-controlled double-blind trial,” Journal of the Neurological Sciences 238 (2005) 31 – 39; Chen et al. “Neuroprotection by Sildenafil: Neuronal Networks Potentiation in Acute Experimental Stroke,” CNS Neuroscience & Therapeutics 20 (2014) 40–49; and Al-Mamun “Combination Therapy with a Rho-Kinase Inhibitor (Fasudil) and a PDE5 Inhibitor (Sildenafil) Ameliorates Monocrotaline-Induced Pulmonary Hypertension and Survival in Rats,” Tohoku University 2014, as applied to claims 1-9 and 11-12 above in further view of Lee et al. US 2008/0058384 A1 published March 6, 2008.
Chen, Shibuya, and Al-Mamun render obvious the treatment of ischemic stroke via the synergistic administration of PDE5 inhibitor, Sildenafil, with a ROCK inhibitor, fasudil.
They do not discuss using other known ROCK inhibitors.
Lee teaches the ROCK inhibitors including GSK429286a. Lee discovered novel indazole compounds, which are inhibitors of ROCK activity and show interesting selectivity over ether protein kinases. Such derivatives are useful in the treatment of disorders associated with inappropriate ROCK activity.
Given that fasudil was used as a ROCK inhibitor, one could simply substitute GSK429286a in its place and expect the drug to work the same way, much as substituting ibuprofen for naproxen, they are both NSAIDs and they both are anti-inflammatory through the mechanism of prostaglandin inhibition. Therefore the instant claims drawn to the specific ROCK inhibitor are obvious at the time of filing.
RESPONSE to Applicant’s Arguments: Applicant argues this rejection based on the rationale in the above rejection, which has already been addressed.
Conclusion
No claims allowed.
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/MICHAEL J SCHMITT/ Examiner, Art Unit 1629
/JEFFREY S LUNDGREN/ Supervisory Patent Examiner, Art Unit 1629
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