DETAILED ACTION
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 .
Drawings
Color photographs and color drawings are not accepted in utility applications unless a petition filed under 37 CFR 1.84(a)(2) is granted. Any such petition must be accompanied by the appropriate fee set forth in 37 CFR 1.17(h), one set of color drawings or color photographs, as appropriate, if submitted via the USPTO patent electronic filing system or three sets of color drawings or color photographs, as appropriate, if not submitted via the via USPTO patent electronic filing system, and, unless already present, an amendment to include the following language as the first paragraph of the brief description of the drawings section of the specification:
The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.
Color photographs will be accepted if the conditions for accepting color drawings and black and white photographs have been satisfied. See 37 CFR 1.84(b)(2).
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.
Claims 1 and 3 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by US Patent No. US 5700447 to Bucala et. al. (Bucala’447).
Regarding claims 1 and 3, Bucala’447 teach that the invention of the disclosure relates generally biomolecules and the often consequent formation of advanced glycosylation end products (AGEs), and particularly to the formation of lipid-AGEs and the role that glycosylated lipids and lipoproteins may play as markers and actors in conditions such as atherosclerosis and diabetes. See column 1 lines 28 – 34. Moreover, Bucala’447 teach that early experimental studies suggested that elevated blood glucose levels during focal cerebral ischemia increase the size of the resulting infarction. See column 4 lines 64 – 66. Furthermore, Bucala’447 teach aminoguanidine, as a known inhibitor of advanced glycosylation. See column 5 lines 21 – 22. See claim 1 limitation for an AGE (advanced glycation end-products) scavenger. See claim 3 limitation for an AGE scavenger that is aminoguanidine.
Additionally, Bucala’447 teach a method and corresponding composition for the treatment of stroke comprising administering a stroke-ameliorating or stroke inhibiting amount of an agent capable of averting the occurrence, or beneficially limiting or reducing the size and severity of an ischemic infarct in both diabetic and non-diabetic individuals. See column 5 lines 32 – 39. See claim 1 limitation for a method of treating a subject having a diabetic stroke. Moreover, Bucala’447 teach an embedment of the method comprising administering a therapeutically effective amount of an agent selected from consisting of aminoguanidine, α-hydrazinohistidine, analogs of aminoguanidine, and pharmaceutical compositions. See column 5 lines 39 – 43. See claim 3 limitation for an AGE scavenger that is aminoguanidine.
In particular, Bucala’447 teach that male lewis rats, 270 – 320 g were given either AGE-modified albumin (AGE-alb) or albumin at 235 mg/kg via IV for two hours before severing the right middle cerebral artery. See column 30 lines 58 – 60. Further, Bucala’447 teach that some of the rats were then given aminoguanidine at 450 mg/kg via IV. See column 30 lines 60 – 62. Bucala’447 teach that aminoguanidine prevented the AGE-alb mediated increase in stroke size as compared with rats that didn’t receive aminoguanidine. See column 30 lines 62 – 64. See claim 1 limitation for a method of treating a subject having a diabetic stroke comprising administering an AGE scavenger. See claim 3 limitation for an AGE scavenger that is aminoguanidine. Moreover, Bucala’447 teach that aminoguanidine interferes with the cascade of cytotoxic effects elicited by AGEs in the ischemic penumbra. See column 30 lines 65 – 67. Therefore the prior art teachings of Bucala’447 anticipates the method of claims 1 and 3; thus claims 1 and 3 are rejected as being anticipated under 35 U.S.C. 102(a)(1).
Claim Rejections - 35 USC § 103
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.
Claim 2 is rejected under 35 U.S.C. 103 as being unpatentable over US Patent No. US 5700447 to Bucala et. al. (Bucala’447), as applied to claims 1 and 3 above, and in further view of Labazi et. al. ((2018), Novel RAGE Antagonist, FPS-ZM1, Reverses Mesenteric Arteriolar Remodeling in Type 2 Diabetic db/db Mice, The FASEB Journal, 31, page 673.8; cited on the IDS dated March 5th, 2026) as evidenced by Hong et. al. ((2016), Effects of RAGE-Specific Inhibitor FPS-ZM1 on Amyloid-β Metabolism and AGEs-Induced Inflammation and Oxidative Stress in Rat Hippocampus, Neurochem Res, 41, 1192 – 1199).
The teachings of Bucala’447 as they relate to claim 1, from which claim 2 depends, are given previously in this office action and are fully incorporated here.
However, Bucala’447 fails to teach a method where the RAGE antagonist is an amyloid-β (Aβ) antagonist. See claim 2 limitation.
Nevertheless, Labazi et. al. teach that type II diabetes (T2D) is a major risk factor for cardiovascular diseases. See page 1 paragraph 1. Labazi et. al. teach that activation of AGE receptors (RAGE) was shown to be associated with vascular dysfunction and vascular smooth muscle proliferation, which may result in vascular remodeling. See page 1 paragraph 1. Furthermore, Labazi et. al. teach that aortae and mesenteric arterioles (MA) isolated from 16 week-old lean control mice (Db/db), obese T2D mice (db/db)and T2D mice (db/db+FPS) treated with RAGE antagonist (FPS-ZM1, 1mg/Kg/day ip, 28 days). See page 1 paragraph 1. As evidenced, by Hong et. al., FPS-ZM1, inhibits amyloid-b binding to RAGE. See page 11992 column 1 paragraph 1. Thus, the prior art of Labazi et. al. teach, FPS-ZM1 as an amyloid-β (Aβ) antagonist. See claim 2 limitation a method where the RAGE antagonist is an amyloid-β (Aβ) antagonist. In addition, Labazi et. al. teach that MAs isolated from T2D mice exhibited a significant increase in internal diameter (158±2 in Db/db vs. 208±13 μm in db/db at 100mmHg, p<0.05), external diameter (180±3 in Db/db vs. 233±14 μm in db/db at 100mmHg, p<0.05) and cross-sectional area (CSA) (6066±597 in Db/db vs. 8753±881 μm2 in db/db at 100mmHg, p<0.05). See page 1 paragraph1. Furthermore, Labazi et. al. teach that RAGE antagonism in T2D significantly reduced MAs internal diameter (178±5 in db/db+FPS vs. 208±13 μm in db/db at 100mmHg, p<0.05), external diameter (200±5 in db/db+FPS vs. 233±14 μm in db/db at 100mmHg, p<0.05) and CSA (6453±400 in db/db+FPS vs. 8753±881 μm2 in db/db at 100mmHg, p<0.05). See page 2 paragraph 1. Additionally, Labazi et. al. teach that AGE/RAGE signaling contributes to the microvascular remodeling observed inT2D and that RAGE blockade using a novel antagonist may present a potential therapeutic target to reduce or reverse diabetes-mediated vascular complications. See page 2 paragraph 1.
Therefore, it would have been obvious before the effective filing date of the instant application to modify the invention of Bucala’447 for a method of treating diabetic stroke comprising administering the AGE scavenger aminoguanidine in view of Labazi et. al. to use a RAGE antagonist that is an amyloid-β (Aβ) antagonist. One of ordinary skill in the art would have been motivated to make this modification because activation of AGE receptors (RAGE) was shown to be associated with vascular dysfunction and vascular smooth muscle proliferation. One of ordinary skill in the art would have had a reasonable expectation for success because RAGE antagonism in T2D significantly reduced MAs internal diameter, external diameter and CSA.
Claims 4 – 5 are rejected under 35 U.S.C. 103 as being unpatentable over US Patent No. US 5700447 to Bucala et. al. (Bucala’447), as applied to claims 1 and 3 above, and in further view of Venkat et. al. ((2017), Blood–Brain Barrier Disruption, Vascular Impairment, and Ischemia/ Reperfusion Damage in Diabetic Stroke, Journal of the American Heart Association, 1 – 11).
The teachings of Bucala’447 as they relate to claim 1, from which claims 4 – 5 depend, are given previously in this office action and are fully incorporated here.
While, Bucala’447 the administration of an AGE Scavenger in the treatment of diabatic stroke; the prior art is silent about whether the subject also had hyperglycemia. See claim 4 limitation for a method where the diabetic stroke is stroke with hyperglycemia. See claim 5 limitation for a method where the subject is likely to develop stroke with hyperglycemia or the subject is suffering from stroke with hyperglycemia.
Nevertheless, Venkat et. al. teach that diabetes mellitus (DM) is a chronic, lifelong, severe metabolic health problem characterized by hyperglycemia, attributable to insulin deficiency, insulin resistance, or a combination of both. See page 1 column 1 paragraph 1. Moreover, Venkat et. al. teach that DM raises the risk of cardiovascular and cerebrovascular diseases (such as ischemic stroke) multifolds with approximately 30% of stroke patients have DM, and stroke in diabetic patients follows a specific clinical pattern mostly resulting in poor prognosis. See page 1 column 1 paragraph 1. As a result, Venkat et. al. teach that neurological deficits and fatality rates are significantly higher in patients with stroke who also have DM. See page 1 column 1 paragraph 1. Venkat et. al. teach that experimental studies have shown that DM instigates a cascade of events leading to severe vascular dysfunction, hemorrhage, earlier and more severe white matter injury, and aggravated inflammatory responses compared with non-DM ischemic brain. See page 1 column 1 paragraph 1.
Moreover, Venkat et. al. teach that hyperglycemia in DM causes oxidative stress and depletes pericytes, depletes pericytes from the cerebral microvasculature, which then leads to blood brain barrier (BBB) disruption. See page 2 column 2 paragraph 2. Furthermore, Venkat et. al. teach that using a model of forebrain ischemia in rats, it has been reported that diabetic hyperglycemia suppresses ischemia-induced astrocyte activation, increases astrocyte cell death, damages the astrocyte end-foot lining around cerebral vessels, and the damaged astrocytes exhibit increased withdrawal of the astrocyte end-foot from the cerebral vessel wall. See page 3 column 1 paragraph 1. Additionally, Venkat et. al. teach that in rats with DM, the infarct volume after stroke was found to be directly proportional to increasing levels of hyperglycemia. See page 5 column 2 paragraph 3.
Therefore, it would have been obvious before the effective filing date of the instant application to modify the invention of Bucala’447 for a method of treating diabetic stroke comprising administering the AGE scavenger aminoguanidine in view of Venkat et. al. to treat subjects with a stroke with hyperglycemia and/ or before they develop the stroke with hyperglycemia. One of ordinary skill in the art would have been motivated to make this modification because DM is characterized by hyperglycemia and raises the risk of cardiovascular and cerebrovascular diseases such as ischemic stroke. One of ordinary skill in the art would have had a reasonable expectation for success because diabetic hyperglycemia suppresses ischemia-induced astrocyte activation, increases astrocyte cell death, damages the astrocyte end-foot lining around cerebral vessels, and the damaged astrocytes exhibit increased withdrawal of the astrocyte end-foot from the cerebral vessel wall. Consequently, by targeting this pathway the suppression of astrocyte activation is avoided potential leading to beneficial downstream effects such as maintain the integrity of the BBB.
Conclusion
Claims 1 – 5 are rejected.
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/DAWANNA SHAR-DAY WHITE/Examiner, Art Unit 1627
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