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 .
Election/Restrictions
Applicant’s election of Group (I) in the reply filed on 10/27/2025 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Applicant’s election of acute ischemic stroke, anterior cerebral circulation infarction, non-cardiogenic infarction, moderate severity (NIHSS 5-15 scores), aged 45-85 years, BZP needs to be administered within 24 hours of stroke onset in the reply filed on 10/27/2025 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)). However, the election of acute ischemic stroke, anterior cerebral circulation infarction, non-cardiogenic infarction, moderate severity (NIHSS 5-15 scores), aged 45-85 years, BZP needs to be administered within 24 hours of stroke onset cannot be an election of a disease characteristic because there is no oxford comma or serial comma as the word “and” or “or” is not present. The Oxford comma (or serial comma) is the optional comma placed before the "and" or "or" in a list of three or more items, like in "A, B, and C". Its purpose is to add clarity by preventing ambiguity, especially when items in the list might be phrases themselves, though its use is a stylistic choice, with major style guides often mandating it for clarity. Additionally, aged 45-85 years and BZP needs to be administered within 24 hours of stroke onset cannot be considered characteristics of a disease as they do not characterize the disease. Furthermore, the specification does not describe an Oxford comma or a serial comma separating the final comma at each of the group of characteristics of the disease. Lastly, a single drug cannot treat all types of cardiovascular ischemic disease recited in (6) of claim 7 at once. Therefore, as stated in the 112b rejection below, the elected species is considered to be acute ischemic stroke as one of the disease characteristic species recited in (6) of claim 7 as the Oxford comma or serial comma is interpreted to be “or.”
Claims 21-23 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.
Priority
This application is a U.S. National Stage Application under 35 U.S.C. § 371 of International Application No. PCT/CN2021/127101 which was filed on 28 October 2021, which claims priority from Chinese Application No. 202011195601.4 filed 30 October 2020.
Status of Claims
Claims 1-13 and 21-23 are pending. Claims 14-20 are canceled. Claims 21-23 are withdrawn. Claims 1-13 are examined in accordance to the elected species (acute ischemic stroke).
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 04/27/2023 has been 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.
Claims 2-6, 12, and 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.
Regarding claim 2, the phrase "BZP is 50-500 mg, such as 100-500 mg, 200-500 mg, 250-500 mg, 300-500 mg, 325-475 mg, 350-475 mg, 350-450 mg, 375-450 mg, or 375-425 mg, for example 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg or 500 mg. " renders the claim indefinite because it is unclear whether the limitations following the phrase that includes such as and the phrase that includes for example, are part of the claimed invention. See MPEP § 2173.05(d).
Regarding claim 2, the claim recites the limitation "the daily dose of BZP" in line 1. There is insufficient antecedent basis for this limitation in the claim because daily dose is not recited in claim 1 which claim 2 depends from.
Regarding claim 3, the phrase "BZP is 25-400 mg, such as 50-400 mg, preferably 50-300 mg, more preferably 50-250 mg, even more preferably 100-250 mg, such as 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg or 400 mg; " renders the claim indefinite because it is unclear whether the limitations following the phrase that includes such as, preferably and even more preferably are part of the claimed invention. See MPEP § 2173.05(d).
Regarding claim 3, the claim recites the limitation "the single daily dose of BZP" in line 1. There is insufficient antecedent basis for this limitation in the claim because daily dose is not recited in claim 1 which claim 3 depends from.
Regarding claim 4, the phrase "a dose of 50-250 mg each time, for example, once, twice or three times a day, with a dose of 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg or 250 mg each time" renders the claim indefinite because it is unclear whether the limitations following the phrase that includes for example are part of the claimed invention. See MPEP § 2173.05(d).
Regarding claim 5, the phrase "a dose of 100-250 mg each time, such as twice a day, with a dose of 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg or 250 mg each time, preferably twice a day, with a dose of 200 mg each time" renders the claim indefinite because it is unclear whether the limitations following the phrase that includes such and preferably are part of the claimed invention. See MPEP § 2173.05(d).
Regarding claim 5, the phrase "the disease is acute stroke and related diseases, preferably, the disease is mild or moderate acute ischemic stroke" renders the claim indefinite because it is unclear whether the limitations following the phrase that includes preferably are part of the claimed invention. See MPEP § 2173.05(d).
Regarding claim 6, the term “acute stroke and relative disease” is a relative term which renders the claim indefinite. The term “acute stroke and relative diseases” is not defined by the claim and by the specification, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. In the present case, it is not clear if the related diseases are disease related to the acute stroke or diseases just are related diseases. If the disease is related diseases, then, it is not clear what diseases that are encompassed by related diseases as acute stroke related diseases can include a plethora of diseases such as
Atherosclerosis: The buildup of fatty plaques in the carotid or cerebral arteries, which can narrow vessels or cause clots.
Atrial Fibrillation (AF): An irregular, often rapid heart rate that causes blood to pool in the heart, forming clots that can travel to the brain.
Heart Disease: Coronary artery disease, heart failure, and dilated cardiomyopathy.
Valvular Heart Disease: Damaged heart valves, including rheumatic mitral/aortic valve disease and prosthetic (mechanical) heart valves.
Carotid Artery Dissection: A tear in the wall of the carotid artery.
Small Vessel Disease: Lipohyalinosis and microatheromas, which cause lacunar strokes.
Patent Foramen Ovale (PFO): A hole in the heart that allows clots to travel from veins to the brain.
Hypertensive Vasculopathy: Uncontrolled high blood pressure is the leading cause, weakening vessel walls.
Cerebral Amyloid Angiopathy (CAA): Protein deposits in blood vessel walls that make them brittle and prone to rupturing, often causing lobar hemorrhages.
Intracranial Aneurysm: A weak, bulging spot in an artery wall that ruptures.
Arteriovenous Malformation (AVM): An abnormal tangle of blood vessels connecting arteries and veins.
Cerebral Venous Sinus Thrombosis: A clot in the veins that drains blood from the brain.
Diabetes Mellitus: Increases risk by 2-3 times by damaging blood vessels.
Sickle Cell Disease: Causes abnormal, sickle-shaped red blood cells to block blood vessels, particularly in children.
Dyslipidemia (High Cholesterol): Contributes to plaque buildup.
Coagulopathies: Clotting disorders that can cause bleeding.
Severe Anemia: Can increase blood flow in a way that encourages clotting.
COVID-19: Increases the risk of ischemic stroke due to inflammation and hypercoagulability.
Varicella-Zoster Virus (VZV): Known to cause vasculopathy (inflammation of blood vessels).
Meningitis/Encephalitis: Inflammation of the brain can cause vasculitis and thrombosis.
Cancer: Certain cancers can increase blood coagulability.
Migraine with Aura: Doubles the risk for ischemic stroke.
Brain edema (swelling)
Aspiration pneumonia
Deep venous thrombosis (DVT)
Epileptic seizures
Urinary tract infections (UTI)
Hypoglycemia (low blood sugar)
Seizures (post-ictal state)
Migraine with aura
Brain tumors or abscesses etc.… The specification does not provide a standard for
ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of acute stroke related diseases. However, if the related disease is mild or moderate acute ischemic stroke, then the Examiner interprets it as such. are acute stroke. Furthermore, the term “the disease” (singular) in the claim is defined by its plural form diseases. “A” or “the” disease is construed to be a single disease. So, defining it by multiple diseases renders it indefinite.
Regarding claim 6, the claim recites the limitation "the disease is" in line 1. There is insufficient antecedent basis for this limitation in the claim because disease (singular) is not recited in claim 1 which claim 6 depends from. Claim 1 recites diseases (plural).
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 7 recites
(2) the broad recitation acute ischemic stroke and the claim also recites cerebral anterior circulation infarction which is the narrower statement of the range/limitation;
(2) the broad recitation acute ischemic stroke followed by the narrow recitation cerebral anterior circulation infarction and non-cardiogenic infarction;
(4) the broad recitation acute ischemic stroke followed by the narrow recitations cerebral anterior circulation infarction, non-cardiogenic infarction, and moderate severity (NIHSS 5-15 scores);
(5) the broad recitation acute ischemic stroke followed by the narrow recitations cerebral anterior circulation infarction, non-cardiogenic infarction, moderate severity (NIHSS 5-15 scores), and aged 45-85 years; and
(6) the broad recitation acute ischemic stroke followed by the narrow recitations anterior cerebral circulation infarction, non-cardiogenic infarction, moderate severity (NIHSS 5-15 scores). The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
Moreover, the recitations in (2)-(6) of claim 7 renders the claim indefinite because conjunction “and” or “or” is not recited after the final commas separating each group or entity. A quick search at the specification did not identify or disclose the conjunction “and” or “or” after the final commas of each of the groups (2)-(6). The fact that the conjunction “or” is recited after the semicolon of (5), the fact that aged 45-85 years and BZP needs to be administered within 24 hours of stroke onset are not characteristics of a disease, and the fact that a single drug cannot treat all types of cardiovascular ischemic disease recited in (6) of claim 7 at once, the Examiner interprets the conjunction that is required after the final commas of each group to be “or.” Therefore, the election of acute ischemic stroke, anterior cerebral circulation infarction, non-cardiogenic infarction, moderate severity (NIHSS 5-15 scores), aged 45-85 years, BZP needs to be administered within 24 hours of stroke onset as the characteristic species is construed to be an election of acute ischemic stroke as one of the options recited in (5) of claim 7.
Regarding claim 9, the phrase "the individual has a time from stroke onset to drug administration of not more than 24 hours, preferably the individual is a human patient with a time from stroke onset to drug administration of 6-24 hours" renders the claim indefinite because it is unclear whether the limitations following the phrase that includes preferably are part of the claimed invention. See MPEP § 2173.05(d).
Regarding claim 12, the phrase “BZP is administered by parenteral route, preferably by intravenous injection or intravenous infusion" renders the claim indefinite because it is unclear whether the limitations following the phrase that includes preferably are part of the claimed invention. See MPEP § 2173.05(d).
Regarding claim 13, the phrase “BZP is administered in the form of a pharmaceutical composition such as sterile lyophilized powder or an injection reconstituted from sterile lyophilized powder in a pharmaceutically acceptable liquid carrier" renders the claim indefinite because it is unclear whether the limitations following the phrase that includes such as are part of the claimed invention. See MPEP § 2173.05(d).
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 1-5, 8, and 11-13 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for treating acute ischemic stroke or improving anti-thrombosis, does not reasonably provide enablement for preventing or treating all cardio-cerebral ischemic diseases or improving all cardio-cerebral circulation disorders. With respect to anti-thrombosis, the specification teaches BZP has anti-thrombotic effect. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
There are several guidelines when determining if the specification of an application allows the skilled artisan to practice the invention without undue experimentation. The factors to be considered in determining what constitutes undue experimentation were affirmed by the court in re Wands (8 USPQ2d 1400 (CAFC 1986)). These factors are (1) nature of the invention; (2) state of the prior art; (3) level of one of ordinary skill in the art; (4) level of predictability in the art; (5) amount of direction and guidance provided by the inventor; (6) existence of working examples; (7) breadth of claims; and (8) quantity of experimentation needed to make or use the invention based on the content of the disclosure.
(1) Nature of the invention
The claims are directed to preventing or treating all cardio-cerebral ischemic diseases or improving all cardio-cerebral circulation disorders or anti-thrombosis with BZP compound.
(2) State of the prior art
The state of the art is that potassium dl-2- (α-hydroxy pentyl) benzoate also referred as dl-PHPB, the claimed compound is effective for reducing cerebral tissue injury induced by MCAO and decreased the infarction areas in a MCAO rat model and also inhibit platelet aggregation. (See Examples 1 and 2 of Yang et al US7,550,507B2.) The MCAO rat model according to the Abstract of Gubskiy et al (Original Article, Open access, published: 25 November 2017, Volume 9, pages 417–425, (2018) closely imitates acute ischemic stroke.
Thus, one cannot ascertain whether the instant invention is of use of BZP for treating all cardio-cerebral ischemic diseases or improving all cardio-cerebral circulation disorders or anti-thrombosis
(3) Level of one of ordinary skill in the art
The level of skill in the art is deemed to be high, generally that of a medical Doctor specializing in the field of vascular neurology.
(4) Level of predictability in the art
The art pertaining to the use of BPZ for treating or preventing all cardio-cerebral ischemic diseases or improving all cardio-cerebral circulation disorders is highly unpredictable. Specifically, namely Bath et al (Int J Stroke. 2015 Mar 2;10(4):469–478) teaches there are no established therapeutic strategies for either preventing or treating SVD (small vesicles disease) although more information about strategies to avoid and that show promise are emerging. (See Conclusions Section.) Small vesicle disease is a major type of cardio-cerebral ischemic disease.
Gao et al (Front Cardiovasc Med. 2025 Mar 25; 12:1507665 pages 1-10) teaches this review systematically summarized the definition, epidemiological features, pathogenesis and therapeutic strategies, and prognosis of Cardio-cerebral infarction (CCI), providing an evidence-based foundation for clinical practice and outlining directions for future research. CCI, characterized by the concurrent or sequential occurrence of AMI and AIS, involves a range of complex pathophysiological mechanisms, including atherosclerosis, neurogenic factors, inflammation, cardiac factors, and certain systemic diseases. Although significant progress has been made in understanding CCI, numerous challenges remain. For instance, classification criteria are not yet standardized, and there is currently no consensus on the optimal diagnostic approach for CCI, given the variability in healthcare settings, resources, and expertise across different regions. Specific treatment guidelines are lacking, treatment strategies remain controversial, and additional high-quality prospective studies are needed to develop approaches for improving long-term outcomes. (See the first paragraph of the conclusions Section.)
In sum, a person of ordinary skill in the art would not expect that BPZ compound to treat or prevent all cardio-cerebral ischemic diseases or improving all cardio-cerebral circulation disorders.
(5) Amount of direction and guidance provided by the inventor
The claims encompass a vast number of cardio-cerebral ischemic diseases or cardio-cerebral circulation disorders or anti-thrombosis. Applicant’s limited guidance does not enable the public to use the claimed BPZ compound for treating or preventing CCI and SVD. There is no directional guidance for the treatment of all cardio-cerebral ischemic diseases or improving all cardio-cerebral circulation disorders. Hence, there is no enablement for a single drug such as BPZ compound to effectively treat of all types of cardio-cerebral ischemic diseases or improving all types of cardio-cerebral circulation disorders.
(6) Existence of working examples
The claims encompass a vast number of cardio-cerebral ischemic diseases or cardio-cerebral circulation disorders that lacks the utility. Applicant’s limited working examples do not enable the public to use such prevention or treatment of all cardio-cerebral ischemic diseases or improving all cardio-cerebral circulation disorders. While Applicant’s claims encompass a plethora of possible cardio-cerebral ischemic diseases or cardio-cerebral circulation disorders, the specification only provides guidance of a particular intravenous administration of 100 mg bid and 200 mg bid for the treatment of acute ischemic stroke.
(7) Breadth of claims
The claims are extremely broad due to the vast number of possible cardio-cerebral ischemic diseases or cardio-cerebral circulation disorders.
(8) Quantity of experimentation needed to make or use the invention based on the content of the disclosure
The specification does not enable any person skilled in the art to which it pertains to make and use the invention commensurate in scope with the claims because using an amount of BZP and any route of administration for the treatment or prevention of possible cardio-cerebral ischemic diseases or cardio-cerebral circulation disorders. In particular, the specification fails to enable the skilled artisan to practice the invention without undue experimentation to use BPZ of the instant invention for preventing or treating all possible cardio-cerebral ischemic diseases or improving all possible cardio-cerebral circulation disorders. Furthermore, based on the unpredictable nature of the invention, the state of the prior art, and the extreme breadth of the claims, one skilled in the art could not perform the claimed invention without undue experimentation.
Claim Interpretation
The claimed preventing or treating cardio-cerebral ischemic diseases (plural) and improving cardio-cerebral circulation disorders (plural) in this application are given their broadest reasonable interpretation using the plain meaning of the claim language in light of the specification as it would be understood by one of ordinary skill in the art. The broadest reasonable interpretation of said claim element is limited by the description in the specification. However, the specification and claim 6 only describe the disease is acute stroke and related diseases. In a preferred embodiment, the disease is mild or moderate acute ischemic stroke. Example 6 of the specification teaches the subject to be a subject with acute ischemic stroke was treated with intravenous BZP at a dose of 100 mg Bid and a dose of 200 mg bid. Nowhere the specification teaches BZP can treat or prevent all the diseases encompassed by preventing or treating cardio-cerebral ischemic diseases (plural) and improving cardio-cerebral circulation disorders (plural). In light of the specification and claim 6, the recitation cardio-cerebral ischemic diseases or improving cardio-cerebral circulation disorders is interpreted to be acute ischemic stroke mild or moderate.
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 1-2 and 10-13 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Chang et al (CN101402565A.). Chang is cited in the IDS filed on 07/27/2023. However, an English translation is cited in the 892-form.
Chang teaches the use of halogen-substituted 2- (α-hydroxy pentyl) benzoate compound for preventing and treating cardio-ischemic diseases and improving heart and antithrombotic. (See third paragraph under Description.) Moreover, Chang teaches potassium 5-bromo-2- (α-hydroxy pentyl) benzoate is the preferred halogen-substituted 2- (α-hydroxy pentyl) benzoate compound. (See Experimental result 2.) Chang also teaches the compound is administered in the form of an intravenous composition at a preferred daily dose of 100 mg, (See Eighth paragraph of page 6.) Furthermore, Chang teaches the preparation of the intravenous injection comprising the compound dissolved in water for injection, regulates pH 8.5-9.5 with sodium hydroxide. The solution was filtered and freeze-dried to afford a cake or powder. The lyophilized injection can be injected and transfused intravenously after it is solved in the 0.9% NaCl solution for injection or 5% glucose injection. (See Example or embodiment 9 of page 9.)
Accordingly, while Chang does not expressly teach administration an effective amount of BZP for improving anti-thrombosis, a person of ordinary skill in the art would “at once envisage” to improve anti-thrombosis with an intravenous injection of 100 mg BZP because Chang clearly teaches halogen-substituted 2- (α-hydroxy pentyl) benzoate compound for preventing and treating cardio-ischemic diseases and improving heart and antithrombotic, the halogen-substituted 2- (α-hydroxy pentyl) benzoate is preferably BZP and said compound is formulated as an intravenous injection with a preferred daily amount of 100 mg.
Lastly, with respect to “the treatment achieves one or more of the following improved effects in the individual:(1) Improving the neurological function score and reducing the NIHSS score; (2) Improving neurological function outcomes and reducing mRS scores; (3) Reducing the volume of cerebral infarction; (4) Reducing the recurrence of ischemic stroke; (5) Reducing the hemorrhagic transformation of ischemic stroke, including symptomatic intracranial hemorrhage and asymptomatic hemorrhagic transformation; and/or (6) Reducing the mortality of ischemic stroke” and “the dosage regimen has a lower incidence of adverse events than other dosage regimens and achieves better improved effects than other dosage regimens”; these limitations simply express the intended outcome of the method step positively recited. Since the method step of the prior is the same as the method with the same dosage regimen claimed, said intended outcome would naturally from the method of Chang.
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.
Claims 1-13 are rejected under 35 U.S.C. 103 as being unpatentable over Chang et al (CN101402565A) in view of Tian et al (Molecules 2016, 21, 501, pages 1-12) and Rehani et al (Neurohospitalist. 2019 Aug 19;10(1):29–37)
Chang teaches the use of the halogenated 2- (α-hydroxy pentyl) benzoate compound for the preparation of a medicament for treating and preventing heart and cerebral ischemic diseases, improving cardio-cerebral circulation disturbance and resisting thrombus (See Abstract.) Moreover, Chang teaches potassium or sodium of 5-bromo-2- (α-hydroxy pentyl) benzoate is the preferred halogen-substituted 2- (α-hydroxy pentyl) benzoate compound. (See second paragraph of page 3 and Experimental result 2.) Chang also teaches the amount of the compound of the present invention to be used may vary depending on the route of administration, the age and weight of the patient, the type and severity of the disease to be treated, and the daily dose may be from 200 to 600 mg, preferably 100 mg, and may be used in one portion or in multiple portions and can be administered in the form of an intravenous composition at a preferred daily dose of 100 mg, (See fourth paragraph of page 4.) Furthermore, Chang teaches the preparation of the intravenous injection comprising the compound dissolved in water for injection, regulates pH 8.5-9.5 with sodium hydroxide. The solution was filtered and freeze-dried to afford a cake or powder. The lyophilized injection can be injected and transfused intravenously after it is solved in the 0.9% NaCl solution for injection or 5% glucose injection. (See Example 9.)
Chang does not teach mild or moderate acute ischemic stroke. Chang does not teach the patient is a human and administration of the 100 mg once or twice daily. Moreover, Chang does not teach the patient has a time from stroke onset to drug administration of not more than 24 hours, preferably the individual is a human patient with a time from stroke onset to drug administration of 6-24 hours.
Tian teaches Brozopentyl sodium salt, sodium (+/-)-5-bromo-2- (α-hydroxy pentyl) benzoate (BZP), derived from NBP, is a novel agent that shows promising outcomes for the treatment of ischemic stroke. (Last paragraph of page 1 and Figure 1.)
Rehani teaches that administration of intravenous thrombolysis was successful within 24 hours of stroke onset in some human patients. The salvageability of brain tissue largely depends on the degree of collateral perfusion of the ischemic territory. Individual patient variability in diffusion/perfusion mismatch volume on advanced imaging will direct subsequent treatment. Given this new data, the clinician and radiologist should be prepared to screen and administer thrombolytic or endovascular therapy within 24 hours of stroke onset. (Second paragraph of the left column of page 30.) Moreover, Rehani teaches there is variation in the time window for BAT treatment. The Madrid Stroke Network consensus protocol for treating BAT (Basilar artery thrombosis) includes selection criteria of (1) confirmation of large vessel occlusion on CT angiography, (2) moderate-to-severe neurological deficit, and (3) 12 hours from symptom onset. Additional centers use a time window of up to 24 hours after symptom onset due to collateral circulation and retrograde filling of the distal basilar artery that may still perfuse the brainstem. (Third paragraph of the right column of page 34.)
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to administer Brozopentyl sodium salt once or twice daily each time in a human patient for treating mild to moderate acute ischemic stroke with a time from stroke onset to drug administration of 6-24 hours to give Applicant’s claimed method. One would have been motivated to do so, not only because Chang teaches the 100 mg of the potassium or sodium of 5-bromo-2- (α-hydroxy pentyl) benzoate can be administered on one portion or multiple portions in a patient where the multiple portions can embrace twice daily and where the patient can contemplate a human patient, but also because Tian teaches Brozopentyl sodium salt, sodium (+/-)-5-bromo-2- (α-hydroxy pentyl) benzoate (BZP) is a novel agent that shows promising outcomes for the treatment of ischemic stroke and also because Rehani teaches BAT (Basilar artery thrombosis) includes selection criteria of (1) confirmation of large vessel occlusion on CT angiography, (2) moderate-to-severe neurological deficit, and (3) 12 hours from symptom onset. Additional centers use a time window of up to 24 hours after symptom onset due to collateral circulation and retrograde filling of the distal basilar artery that may still perfuse the brainstem. One would reasonably expect the administration of Brozopentyl sodium salt once or twice daily each time in a human patient for successfully treating mild to moderate acute ischemic stroke with a time from stroke onset of 6-24 hours in order to avoid further brain damage caused by the moderate to severe stroke.
Accordingly, with respect to “the treatment achieves one or more of the following improved effects in the individual:(1) Improving the neurological function score and reducing the NIHSS score; (2) Improving neurological function outcomes and reducing mRS scores; (3) Reducing the volume of cerebral infarction; (4) Reducing the recurrence of ischemic stroke; (5) Reducing the hemorrhagic transformation of ischemic stroke, including symptomatic intracranial hemorrhage and asymptomatic hemorrhagic transformation; and/or (6) Reducing the mortality of ischemic stroke” and “the dosage regimen has a lower incidence of adverse events than other dosage regimens and achieves better improved effects than other dosage regimens”; these limitations simply express the intended outcome of the method step positively recited. Since the claimed method step is obvious over method taught by the cited references, said intended outcome would naturally from the method of Chang, Tian, and Rehani.
Conclusion
Claims 1-13 are not allowed.
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/JEAN P CORNET/ Primary Examiner, Art Unit 1628