DETAILED ACTION
Claims 1-11 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 7/12/2023 is a National Stage entry of CT/CN2022/071541, International Filing Date of 1/12/2022 and claims foreign priority to 202110039436.1, filed 1/13/2021.
Information Disclosure Statement
The Information Disclosure Statements (IDS) submitted on 7/12/2023, 11/17/2023, 5/17/2024, 8/26/2024, and 10/24/2025 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the Information Disclosure Statements are being considered by the Examiner.
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.
Claim 8 is 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.
Claim 8 requires, “in a weight ratio of 1:1, 3:1, 9:1, 10:1 and/or 18:1.” This language is unclear as one would not understand having 2 ratios in the same composition. Applicant should simple state “or” not “and/or” to overcome this rejection.
Claims 10 and 11 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.
Regarding both claims, they state the phrase "preferably, the cerebrovascular disease is selected from ischemic cerebrovascular disease; preferably, the ischemic cerebrovascular disease is selected from ischemic stroke," renders the claim indefinite because it is unclear whether the limitations following the phrase (“preferably”) are part of the claimed invention. See MPEP § 2173.05(d).
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 1 and 9-11 are rejected under 35 U.S.C. 103 as being unpatentable over
Takagi et al. “Protective effects of cilostazol against hemorrhagic stroke: Current and future perspectives,” Journal of Pharmacological Sciences 131 (2016) 155e161;
Chen et al. “Borneol for Regulating the Permeability of the Blood-Brain Barrier in Experimental Ischemic Stroke: Preclinical Evidence and Possible Mechanism,” Hindawi Oxidative Medicine and Cellular Longevity Volume 2019, Article ID 2936737, 15 pages;
Claim 1 is directed towards a composition comprising the following components: component (I), cilostazol, a derivative, a pharmaceutically acceptable salt, a stereoisomer, or a prodrug molecule thereof; and component (II), (+)-2-bomeol, borneol, or a drug with an active ingredient of (+)-2-bomeol.
Takagi teaches cilostazol is a phosphodiesterase-3 inhibitor and is known to have pleiotropic effects including antiplatelet and vasodilatation effects and protective effects on endothelial cells. Cilostazol also reportedly reduced stroke recurrence, poststroke intracranial hemorrhage, and extracranial bleeding in a meta-analysis. Takagi looks in to the research on the drug, Cilostazol, and concludes stating, “These results suggested that cilostazol reduces hemorrhagic stroke by protecting the entire blood-brain barrier.“
Takagi doesn’t combine borneol with cilostazol.
Chen teaches in a review article that borneol is indicated for the treatment of ischemic stroke. Chen provides background on the mechanism of action, stating: “During the cerebral ischemia/reperfusion injury, changes in BBB structures result in the increase of its permeability and the loss of its protective function, which may deteriorate the tissue injury [5, 6]. Thus, the disruption of BBB is an essential pathological basis of cerebral ischemic injury.” Chen teaches “borneol can alleviate the BBB disruption and plays a protective role on cerebral ischemic injury through multiple signaling pathways.”
"It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980) (citations omitted) (Claims to a process of preparing a spray-dried detergent by mixing together two conventional spray-dried detergents were held to be prima facie obvious.). See also In re Crockett, 279 F.2d 274, 126 USPQ 186 (CCPA 1960) (Claims directed to a method and material for treating cast iron using a mixture comprising calcium carbide and magnesium oxide were held unpatentable over prior art disclosures that the aforementioned components individually promote the formation of a nodular structure in cast iron.); Ex parte Quadranti, 25 USPQ2d 1071 (Bd. Pat. App. & Inter. 1992) (mixture of two known herbicides held prima facie obvious); and In re Couvaras, 70 F.4th 1374, 1378-79, 2023 USPQ2d 697 (Fed. Cir. 2023) (That the two claimed types of active agents, GABA-a agonists and ARBs, were known to be useful for the same purpose—alleviating hypertension—alone can serve as a motivation to combine).
Claim 1 was prima facie obvious at the time of filing as the claim is directed towards a composition of 2 compounds (cilostazol and borneol) both used for the same indication/purpose as they both are taught to be used for ischemic stroke by protecting the BBB.
Claim 9 requires a pharmaceutically acceptable adjuvant. Applicant doesn’t define “adjuvant” in the Specification, but notes that borneol is a FDA approved adjuvant in the Background Section and states this is from 2020 (therefore prior art). As such the composition contains a adjuvant.
Claims 10 and 11 are directed towards treating ischemic stroke with the composition. The art again teaches this indication, and therefore the administration of the composition is obvious based on the teachings above.
Claims 1 and 9-11 are found obvious.
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 1-11 are rejected under 35 U.S.C. 103 as being unpatentable over
Takagi et al. “Protective effects of cilostazol against hemorrhagic stroke: Current and future perspectives,” Journal of Pharmacological Sciences 131 (2016) 155e161;
Chen et al. “Borneol for Regulating the Permeability of the Blood-Brain Barrier in Experimental Ischemic Stroke: Preclinical Evidence and Possible Mechanism,” Hindawi Oxidative Medicine and Cellular Longevity Volume 2019, Article ID 2936737, 15 pages;
As applied to claims 1 and 9-11 above in further view of ClinicalTrials.gov ID
Lee et al. “Cilostazol in Acute lschemic Stroke Treatment (CAIST Trial): A Randomized Double-Blind Non-Inferiority Trial,” Cerebrovasc Dis 2011;32:65-71; and
NCT01929096 (Clinical Trial ‘096) published 7/3/2015.
Claim 1 is directed towards a composition comprising the following components: component (I), cilostazol, a derivative, a pharmaceutically acceptable salt, a stereoisomer, or a prodrug molecule thereof; and component (II), (+)-2-bomeol, borneol, or a drug with an active ingredient of (+)-2-bomeol.
Claims 2-8 are directed towards a ratio of the 2 compounds. The claims require a ratio anywhere from 100:1 to 1:1 of cilostazol: borneol.
The combination of Tagaki and Chen teach the 2 compounds have the same indication and activity in protected the patient with ischemic stroke by protecting the BBB. They do not teach a ratio of the compounds together.
Tagaki does show that cilostazol is given at 1 to 3mg/kg, and Chen teaches that borneol is given in many doses, (1000mg/kg , 600mg/kg, 500mg/kg, 200mg/kg, 66mg/kg, 28mg/kg, 20mg/kg, 10mg/kg, 3mg/kg). This gives the skilled artisan a range to consider and optimize. The simple starting point for the combination would be anywhere from 1:1000 or 3:1000 all the way to 1:3 or 3:3. What is clear from the teaching is that the dose of the drugs would need to be optimized for the patient as one would need to consider routine practice in the art and one would have to find the proper pharmacodynamic to pharmacokinetic balance of effect for toxicity. This would lead to the variation in ratio of the 2 components. Regardless one could arrive at a 1:1 ratio of the 2 components and that ratio would render obvious claims 2-4 and 8.
Lee is brought in to show that in humans the typical dose of cilostazol given to humans for Acute Ischemic Stroke was 200 mg/day.
Clinical Trial ‘096 is brought in to show that (+)-borneol was dose in humans along with edaravone in the doses of 2.5, 7.5, 12.5 mg every 12h. This would roughly equate to 0.031, 0.09, 0.16mg/kg for an 80kg person.
The art recognizes the dose will vary for both compounds indicating a need to optimize the drug dose for effect.
Therefore in this case we have an overlapping range. In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990) (The prior art taught carbon monoxide concentrations of "about 1-5%" while the claim was limited to "more than 5%." The court held that "about 1-5%" allowed for concentrations slightly above 5% thus the ranges overlapped.); In re Geisler, 116 F.3d 1465, 1469-71, 43 USPQ2d 1362, 1365-66 (Fed. Cir. 1997) (Claim reciting thickness of a protective layer as falling within a range of "50 to 100 Angstroms" considered prima facie obvious in view of prior art reference teaching that "for suitable protection, the thickness of the protective layer should be not less than about 10 nm [i.e., 100 Angstroms]." The court stated that "by stating that ‘suitable protection’ is provided if the protective layer is ‘about’ 100 Angstroms thick, [the prior art reference] directly teaches the use of a thickness within [applicant’s] claimed range."). See also In re Bergen, 120 F.2d 329, 332, 49 USPQ 749, 751-52 (CCPA 1941) (The court found that the overlapping endpoint of the prior art and claimed range was sufficient to support an obviousness rejection, particularly when there was no showing of criticality of the claimed range).
Moreover we see the art is showing a need to optimized the dosing range for effect. Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (Claimed process which was performed at a temperature between 40°C and 80°C and an acid concentration between 25% and 70% was held to be prima facie obvious over a reference process which differed from the claims only in that the reference process was performed at a temperature of 100°C and an acid concentration of 10%.); see also Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 ("The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages."); In re Hoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969) (Claimed elastomeric polyurethanes which fell within the broad scope of the references were held to be unpatentable thereover because, among other reasons, there was no evidence of the criticality of the claimed ranges of molecular weight or molar proportions.). For more recent cases applying this principle, see Merck & Co. Inc. v. Biocraft Lab. Inc., 874 F.2d 804, 809, 10 USPQ2d 1843, 1848 (Fed. Cir. 1989), cert. denied, 493 U.S. 975 (1989)(Claimed ratios were obvious as being reached by routine procedures and producing predictable results); In re Kulling, 897 F.2d 1147, 1149, 14 USPQ2d 1056, 1058 (Fed. Cir. 1990)(Claimed amount of wash solution was found to be unpatentable as a matter of routine optimization in the pertinent art, further supported by the prior art disclosure of the need to avoid undue amounts of wash solution); and In re Geisler, 116 F.3d 1465, 1470, 43 USPQ2d 1362, 1366 (Fed. Cir. 1997)(Claims were unpatentable because appellants failed to submit evidence of criticality to demonstrate that that the wear resistance of the protective layer in the claimed thickness range of 50-100 Angstroms was "unexpectedly good"); Smith v. Nichols, 88 U.S. 112, 118-19 (1874) (a change in form, proportions, or degree "will not sustain a patent"); In re Williams, 36 F.2d 436, 438, 4 USPQ 237 (CCPA 1929) ("It is a settled principle of law that a mere carrying forward of an original patented conception involving only change of form, proportions, or degree, or the substitution of equivalents doing the same thing as the original invention, by substantially the same means, is not such an invention as will sustain a patent, even though the changes of the kind may produce better results than prior inventions."). See also KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 416, 82 USPQ2d 1385, 1395 (2007) (identifying "the need for caution in granting a patent based on the combination of elements found in the prior art.").
Given this set of facts, the claims directed to the range of ratios is prima facie obvious at the time of filing.
Notes on a Reference
A reference, Zhang, J. L., H. J. Fu, and L. B. Zhao. “Effects of tongxinluo and cilostazol on the treatment of patients with cerebral infarction,” Guide of China Medicine 8.21 (2010): 16-18, came up in the search several times and indicated the combination of Tongxinluo and cilostazol were used for Patients with Cerebral Infarction. Tongxinluo contains borneol. After getting the reference, the two drugs were not combined, the reference clearly indicated they were tried separately. As such this is not anticipatory, even tough several sources citing this reference alluded to the drugs being used in combination.
Conclusion
No claims allowed.
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/MICHAEL J SCHMITT/Examiner, Art Unit 1629
/JEFFREY S LUNDGREN/Supervisory Patent Examiner, Art Unit 1629