DETAILED ACTION
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 19 August 2026 has been entered.
This Office Action is in response to Applicant’s Amendment and Remarks filed on 19 August 2026 in which claims 16 and 82 were canceled, claim 1 was amended to change the scope and breadth of the claims, and claim 85 was newly added.
Claims 1, 4-12, 15, 24, 28, 29, 32, 34 and 83-85 are pending in the current application and are examined on the merits herein.
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 .
Withdrawn Rejections
Applicant’s arguments, filed 19 August 2026, with respect to the rejection of claims 1, 4, 5, 11, 12, 15, 16, 28, 29, 32, 34, 83 and 85 under 35 U.S.C. § 102(a)(1)/(a)(2) as being anticipated by Huizing, has been fully considered and is persuasive. Applicant contends Huizing does not expressly disclose the pH of the solution. The rejection is hereby withdrawn.
Applicant’s Declaration, filed 19 August 2026 and 09 March 2026, with respect to the rejection of claims 1, 4, 5, 11, 12, 15, 16, 28, 29, 32, 34 and 82-84 under 35 U.S.C. § 103 as being unpatentable over Huizing et al. in view of Hsieh et al., has been fully considered and is persuasive.
Applicant contends mannosamine and N-acetyl mannosamine demonstrated different effects in a brain stroke model. Specifically, when the same amount of mannosamine and N-acetyl mannosamine were tested in a transient middle cerebral artery occlusion (tMCAO) model, Applicant found mannosamine treatment reduced permeability as indicated by a noticeable reduction in Evans blue leakage compared to PBS-treated control (see paragraphs 4 and 5 of the 19 August 2026 declaration). On the other hand, N-acetyl mannosamine treatment did not reduce permeability.
Thus, the data demonstrates the two substances do not have similar effects in a stroke model, and are therefore not obvious alternatives for the treatment of stroke. Since Huizing et al. do not exemplify treating stroke with mannosamine, and in light of the data presented in the declaration, there does not appear to be a reasonable expectation of success in treating stroke with D-mannosamine.
The rejection is hereby withdrawn.
New Rejections
Claim Rejections - 35 USC § 112(b)
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 12 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.
The recitation “wherein the single dosing treatment regimen…comprises pretreatment…in relation to an ischemic event affecting a brain of the subject” in claim 12 renders the claim herein indefinite, because it appears to be directed towards preventing a stroke, whereas independent claim 1 is directed to treating a stroke, as in, it has occurred.
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.
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.
Claim(s) 1, 4, 5, 11, 12, 15, 24, 28, 29, 32, 34 and 83-85 are rejected under 35 U.S.C. 103 as being unpatentable over Zhong et al. (Nature Communications, vol. 11, 6330, 21 pages, cited in PTO-892) in view of Hsieh et al. (US Patent Application Publication No. 2021/0379151, cited in previous Office Action), and further in view of Zhenghong et al. (CN102119935, full Espacenet machine translation cited in PTO-892).
Zhong et al. found hexosamine D-mannosamine (ManN) is an endothelial cell (EC) mitogen, with an additivity with VEGF (abstract; p.10, left column). Zhong et al. showed ManN has a “unique ability to inhibit protein post-translation modifications, activate stress pathways, and show additivity with VEGF in promoting EC proliferation and angiogenesis.” (p.13, Discussion). ManN inhibits glycosylation in ECs, and stimulates EC proliferation via both HNK activation and the unfolded protein response caused by ER stress (abstract). It resulted in enhanced angiogenesis in a mouse ischemia model (abstract). Thus, activation of stress pathways followed by glycosylation inhibition can promote EC proliferation and angiogenesis, and “may represent a therapeutic strategy for treatment of ischemic disorders”. Zhong et al. also confirmed VEGF induced vascular permeability (p.10, second para).
Zhong et al. teach “activation of the JNK/c-Jun and UPR pathways in BCECs was unique to ManN as well as the glycosylation inhibitors” (p.13, third para). Zhong et al. teach “angiogenesis has the potential of providing a therapeutic benefit to patients with ischemic disorders such as peripheral arterial disease (PAD) or coronary ischemia” (p.15, first para). Zhong et al. teach “The lack of direct permeability-enhancing effects of ManN may prove valuable, since it is expected to result in less edematous tissues…It is tempting to speculate than an endothelial cell mitogen like ManN, devoid of permeabilizing effects, may help protect and stabilize blood vessels and thus limit tissue damage” (p.15, third para).
Zhong et al. do not expressly disclose the ManN in a solution of pH 5.0 to 8.0, or treating stroke (claim 1).
Hsieh et al. teach a method for delivering a therapeutic agent to the brain of a subject, the method comprising administering a VEGF polypeptide systemically to a subject in need thereof, administering to the subject systemically an effective amount of a therapeutic agent, and then administering a second dose of a VEGF polypeptide (claim 1). The subject is a human patient, having, or is at risk for a brain stroke (claim 17). The term “stroke” may be referred to as ischemic stroke, and includes thrombotic stroke (para [0107]). Hsieh et al. teach VEGF derivatives create a transient window, during which the blood brain barrier (BBB) has enhanced permeability, allowing for entry of therapeutic agents into the brain (para [0006]). The active ingredient can be formulated at a pH of 5.5 to 8.0 (para [0080]). Hsieh et al. teach one or more active agents may be formulated into solutions (para [0083], [0089]).
Zhenghong et al. teach the use of tunicamycin for treating ischemic cerebral stroke (claim 1). Zhenghong et al. teach tunicamycin is a glycosylation inhibitor, and activates ER stress pathway (para [0007]).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to administer a ManN and a VEGF derivative to a subject to treat thrombotic stroke.
In the same field as Zhong et al. for treating ischemic conditions with a glycosylation inhibitor, the ordinary artisan would have known from Zhenghong et al., that tunicamycin was successfully used as a glycosylation inhibitor to treat ischemic stroke. Thus, they are recognized by the art as alternative glycosylation inhibitors for treating ischemic conditions. Furthermore, both Zhong et al. and Zhenghong et al. teach a glycosylation inhibitor that also functions to activate the ER stress pathway. Moreover, ManN demonstrated an additive effect for treating ischemic conditions, when combined with VEGF. The ordinary artisan would have known VEGF derivatives can be administered to a subject suffering from, or at risk from a stroke to increase the permeability of the BBB to therapeutic active agents.
The ordinary artisan would have been motivated to administer a composition comprising ManN and VEGF, because ManN is recognized as the active agent for inhibiting glycosylation, activating ER stress, and promoting angiogenesis to treat ischemia, because Zhong et al. teach ManN and VEGF have an additive effect towards treating ischemic conditions, VEGF has been used in combination with active agents for treating ischemic stroke, and Zhendong et al. teach glycosylation inhibitors for treating stroke. The ordinary artisan would have been motivated to administer a composition comprising ManN and VEGF, wherein the ManN is administered as a composition that consists essentially of ManN (and without concurrent administration of a different hexosamine), because it is recognized as the active agent for inhibiting glycosylation, activating ER stress, and promoting angiogenesis to treat ischemia. Furthermore, the ordinary artisan would have been motivated to administer ManN as the only glycosylation inhibitor, because it was found to be effective on its own. Similarly, Zhenghong et al. teach administering tunicamycin as the sole glycosylation inhibitor to treat ischemic stroke. Thus, the ordinary artisan would have had a reasonable expectation of success in substituting one glycosylation inhibitor for another.
The ordinary artisan would have had a reasonable expectation of success in administering both ManN and VEGF for treating an ischemic stroke because VEGF was successfully used in combination with therapeutic agents to treat stroke, tunicamycin, another glycosylation inhibitor/ER stress activator was taught for treating ischemic stroke, and ManN was found effective in treating other ischemic conditions.
One having ordinary skill in the art would have been motivated to administer mannosamine in the form of a solution, because Huizing et al. expressly teach it as an optional formulation. The ordinary artisan would have been motivated to administer mannosamine in a solution at a pH of around 7, to ensure it is at an acceptable physiologically pH that is safe for oral administration. Additionally, Hsieh et al. teach the VEGF and active agent for treating stroke can be formulated as a solution, wherein the pH for the active agent ranges from 5.5 to 8.0.
The recitation “for reducing disruption of the blood-brain barrier in stroke, the method comprising administering to a subject in need thereof” in claim 1, is broadly and reasonably interpreted as an intended use of administering the claimed composition to a subject having stroke.
Thus, the claimed invention as a whole is prima facie obvious over the combined teaching of the prior art.
Conclusion
In view of the rejections to the pending claims set forth above, no claim is allowed.
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/BAHAR CRAIGO/
Primary Examiner
Art Unit 1699
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