DETAILED ACTION
Claims 1-13 were pending; claims 1, 5, 7-8, and 10 have been amended per the Reply of 5/28/2026.
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 .
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 § 112
(NEW Rejection)
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.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
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 of carrying out his invention.
Claims 1-4, 6-9, and 11-13 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Independent claims 1, 7, and 8 all require the limitation of “a selective pan-Rho-associated kinase (pan-ROCK) inhibitor.” Applicant supports this limitation with para [0047], reproduced below:
[0047] In the present invention, a “Rho-associated kinase (ROCK) inhibitor” is a material having a function of suppressing apoptosis, and is known to have functions, such as neurocladism, myosin phosphorylation, and suppression of agonist-induced Ca2+ sensitization in smooth muscle contraction. More specifically, the ROCK inhibitor has been reported to have functions of alleviating the abnormal structure of muscle cells that cause hypertension and asthma, increasing blood flow in the optic disc, and continuously reducing intraocular pressure, and examples thereof include fasudil, ripasudil, RKI-1447, Y-27632, GSK429286A, Y-30141 and the like, and may preferably be N-(6-fluoro-1H-indazol-5-yl)-6-methyl-2-oxo-4-[4-(trifluoromethyl)phenyl]-3,4-dihydro-1H-pyridine-5-carboxamide (GS K429286A) represented by the following Chemical Formula 1, but are not limited thereto.
Applicant has not defined “selective” or “pan” in the Specificaiton. Applicant’s arguments state:
“Selective pan-ROCK inhibitors, as recited in amended claim 1, are "pan-inhibitors" because they target both ROCK1 and ROCK2, but they are regarded by those having ordinary skill in the art as "selective" because they demonstrate significantly higher affinity for ROCK kinases over other AGC kinases like PKA or PKC. Fasudil is a pan-ROCK inhibitor which targets ROCK's ATP-dependent kinase domain as well as other serine- threonine kinases such as PKA and PKC. Therefore, while fasudil is a pan-ROCK inhibitor, fasudil is considered a non-selective pan-ROCK inhibitor where non-selective refers to other kinases. In contrast, selective pan-ROCK inhibitors, such as GSK429286A, are characterized by high selectivity for the ROCK family (both ROCK1/2 isoforms) compared to other kinases thereby avoiding the off-target effects caused by Fasudil's non-selective binding with other serine-threonine kinases (PKA/PKC inhibition).”
The claims are rejected for Written Description as Applicant does not have support for this new genus of compounds claimed. Applicant’s arguments are not used for Written Description, and Applicant has not shown this narrower genus in the Specification or Original Claims. Applicant can limit the Markush claim, instant claim 5, but Applicant cannot introduce a new genus that has not been described or taught in the Specification or Original Claims.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-4, 6-9, and 11-13 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Independent claims 1, 7, and 8 all require the limitation of “a selective pan-Rho-associated kinase (pan-ROCK) inhibitor.” The metes and bounds of this claim term are not defined with clear metes and bounds as the potency required by the term is unclear. Applicant has argues the following:
“Selective pan-ROCK inhibitors, as recited in amended claim 1, are "pan-inhibitors" because they target both ROCK1 and ROCK2, but they are regarded by those having ordinary skill in the art as "selective" because they demonstrate significantly higher affinity for ROCK kinases over other AGC kinases like PKA or PKC. Fasudil is a pan-ROCK inhibitor which targets ROCK's ATP-dependent kinase domain as well as other serine- threonine kinases such as PKA and PKC. Therefore, while fasudil is a pan-ROCK inhibitor, fasudil is considered a non-selective pan-ROCK inhibitor where non-selective refers to other kinases. In contrast, selective pan-ROCK inhibitors, such as GSK429286A, are characterized by high selectivity for the ROCK family (both ROCK1/2 isoforms) compared to other kinases thereby avoiding the off-target effects caused by Fasudil's non-selective binding with other serine-threonine kinases (PKA/PKC inhibition).”
The problem is Applicant has introduced “pan” to mean the compound targets both ROCK1 and ROCK2, but Applicant has not defined the required potency of the targeting, or if the compound must have similar activity on both. This leaves this claim term ambiguous. Moreover, Applicant states “selective” to mean “they demonstrate significantly higher affinity for ROCK kinases over other AGC kinases like PKA or PKC.” The problem though is Applicnat has not taught how much more potent on ROCK1 and ROCK2 compared to these other kinases, or other targets in general. For example, Applicant has made the claim unclear as to if they cover Y-2763 which hits ROCK1 @ 140 nM, ROCK2 @ 300 nM, and >200 fold less activity on PKA/PKC/MLCK. While, fasudil hits ROCK1 @ 330 nm, ROCK2 @160 nM, and PKA @ 5 micromolar, PKG @ 1.65 micromolar, so while it clearly is selective for ROCK1 & 2 it does have some activity on other kinases. This makes the term selective unclear. The true dividing point is unclear. Applicant has not defined these terms, and selective is not clearly defined. As such the metes and bounds of the term is indefinite.
Claim Rejections - 35 USC § 103
(NEW Rejection)
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 1-4, 6-9, 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; Ming et al. “A Rho-kinase inhibitor reverses learning and memory deficits in a Rat model of chronic cerebral ischemia by altering Bcl-2/Bax-NMDAR signaling in the cerebral cortex,” Journal of Pharmacological Sciences, Volume 138, Issue 2, 2018, Pages 107-115; 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 (a pan ROCK inhibitor).
Ming teaches treating ischemic stroke with Y27632 (a pan-selective-ROCK inhibitor).
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 or Y27632 and sildenafil because the two drugs/pathways 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.”
Ming teaches the use of Y27632 (a pan selective ROCK inhibitor) on middle cerebral artery occlusion (MCAO) model rats and observed that their data provides evidence supporting the hypothesis that Rho-kinase inhibitors exert neuroprotective effects on cerebral ischemia.
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 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 selective pan ROCK inhibitors were not taught in the art for ischemic stroke, Ming is brought in to show the use of Y27632 (a pan-selective-ROCK inhibitor) in the model of ischemic stroke. Given the art teaches the activity coming from ROCK inhibition, it would be obvious to use any ROCK inhibitor for the treatment, and one would be motivated to use a selective compound to avoid off target effects.
Claim Rejections - 35 USC § 103
(NEW 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; Ming et al. “A Rho-kinase inhibitor reverses learning and memory deficits in a Rat model of chronic cerebral ischemia by altering Bcl-2/Bax-NMDAR signaling in the cerebral cortex,” Journal of Pharmacological Sciences, Volume 138, Issue 2, 2018, Pages 107-115; 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 1-4, 6-9, and 11-13 above in further view of Lee et al. US 2008/0058384 A1 published March 6, 2008.
Chen, Ming, Shibuya, and Al-Mamun render obvious the treatment of ischemic stroke via the synergistic administration of PDE5 inhibitor, Sildenafil, with a ROCK inhibitor, fasudil/ Y27632.
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 either protein kinases. Such derivatives are useful in the treatment of disorders associated with inappropriate ROCK activity.
Given that fasudil and Y27632 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 that selective pan ROCK inhibitors were not taught in the art for ischemic stroke, Ming is brought in to show the use of Y27632 (a pan-selective-ROCK inhibitor) in the model of ischemic stroke. Given the art teaches the activity coming from ROCK inhibition, it would be obvious to use any ROCK inhibitor for the treatment, and one would be motivated to use a selective compound to avoid off target effects.
Conclusion
No claims allowed.
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 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 MICHAEL J SCHMITT whose telephone number is (571)270-7047. The examiner can normally be reached M-F 8-6 MidDay Flex.
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/MICHAEL J SCHMITT/ Examiner, Art Unit 1629
/JEFFREY S LUNDGREN/ Supervisory Patent Examiner, Art Unit 1629
