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), with the addition 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 and maintained.
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 21-29 are pending. Claims 14-20 are canceled. Claims 21-23 are withdrawn. Claims 1-13 and 26-29 are examined in accordance to the elected species (acute ischemic stroke). Acknowledgement is made of the receipt and entry of the amendment to the claims filed on August 03, 2026.
Action Summary
The rejection of claims 2-6, 12, and 13 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph is withdrawn. However, claims 7 and 9 are maintained, but revisited and modified in view of the amendment.
Th rejection of 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, are maintained, but revisited and modified in view of the claim amendment and the newly presented claims.
The rejection of claims 1-2 and 10-13 remain 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 are maintained.
The rejection of claims 1-13 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) are maintained, but revisited and modified in light of the claim amendment.
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 7 and 9 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.
Regard to claim 7, the claim depends from claim 6, which recites that “the disease is acute ischemic stroke,” and further recites that “the disease is characterized by an item selected from the group consisting of “alternatives (1)-(6). However, the recited alternatives do not consistently characterize the disease. Rather, the alternatives progressively recite a combination of characteristics relating to the disease, characteristics relating to an individual, and conditions relating to the administration of BZP. For example, altnerative (4) recites, inter alia, “moderate severity (NIHSS 5-15 scores),” and alternative (6) additionally recites that “BZP needs to be administered within 24 hours of stroke onset.” The recitation “aged 45-85 years” characterizes the individual, rather than the disease, while the requirement that BZP be administered within 24 hours of stroke onset constitutes a condition of administration, rather than a characteristic of the disease. Accordingly, it is unclear what is intended by the limitation of “the disease is a disease characterized by an item selected from the group consisting of” alternatives (1)-(6), because the listed alternatives various recite characteristics of the disease, the individual, and condition of treatment. Therefore, the metes and bounds of claim 7 cannot be determined with reasonable certainty.
With respect to claim 9, the claim depends from claim 1 and recites that “the BZP is administered to the individual within a time of not more than 24 hours” from stroke onset. However, claim 1 recites generally a method for preventing or treating “ a cardio-cerebral ischemic disease” and does not require that the cardio-cerebral ischemic disease being prevented is a stroke. Thus, claim 1 does not necessarily establish “a stroke onset” from which the recited period of not more than 24 hours can be measure. It is therefore unclear how the temporal limitation requiring administration within not more than 24 hours from “stroke onset” applies to embodiments encompassed by claim 1 in which the cardio-cerebral ischemic disease is not a stroke. Accordingly, the metes and bounds of claim 9 cannot be determined with reasonable certainty.
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 7 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claim 7 depends from claim 6. Claim 6 requires that the “disease is acute ischemic stroke.” Claim 7 further recites that “the disease is a disease characterized by an item selected from the group consisting of,” wherein alternative (1) recites “Acute ischemic stroke.” Thus, when claim 7 reads on alternative (1), claim 7 merely repeats the limitation already positively recited in claim 6 and does not specify any further limitation of the subject matter of claim 6 Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim 7 is also rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claim 7 depends from claim 6. Claim 6 requires that the “disease is acute ischemic stroke.” Claim 7 further recites that “the disease is a disease characterized by an item selected from the group consisting of” alternative (1)-(6). To the extent the comma-separated characteristics are intended to represent alternative disease characteristics, such that the commas are construed as “or,” claim 7 encompasses embodiment in which “cerebral anterior circulation infarction,” “non-cardiogenic infarction,” “moderate severity (NIHSS 5-15 scores),” “ aged 45-85 years,” or administration of BZP within 24 hours of stroke onset is selected without necessarily requiring that the disease is acute ischemic stroke. Under that construction, claim 4 fails to include the acute ischemic stroke limitation of claim 6. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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, 11-13, and 26-29 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 with BZP under the disclosed and experimentally supported conditions, does not reasonably provide enablement for the full scope of treating or preventing “a cardio-cerebral ischemic disease” or “cardio-cerebral circulation disorder. 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.
Independent claim 1 recites a method for preventing or treating “a cardi-cerebral ischemic disease” or “cardio-cerebral circulation disorder” in an individual by administering an effective amount of sodium 5-bromo-2-(α-hydroxypenyl) benzoate (BPZ), at a daily dose of 50-500 mg,
Although the claim now uses the singular expression “a cardio-cerebral ischemic disease” or “cardio-cerebral circulation disorder,” the claim is not limited to acute ischemic stroke. Rather, the generic expression encompasses the different cardio-cerebral ischemic diseases falling within the genus.
The issue therefore is not whether the specification enables one embodiment falling within the claim. Rather, the issue is whether the specification reasonably enables the skilled artisan to practice the full scope of the claimed genus without undue experimentation.
The specification provides its substantive experiment in the context of acute ischemic stroke, including particular stroke populations, dosing regimens, severity criteria, timing of administration, and measured neurological outcomes. The presently amended claims themselves reflect this disclosed focus: claim 6 narrows the disease to acute ischemic stroke and claim 7 further identifies particular acute-ischemic-stroke populations and treatment conditions.
Accordingly, the Examiner acknowledges that specification provides substantial greater guidance for the acute ischemic stroke embodiments that for the full genus of cardio-cerebral ischemic diseases encompassed by claim 1. The question presented by claim 1 is therefore whether those teachings may reasonably be extrapolated to treatment or prevention throughout the considerably broader claimed disease genus.
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) breadth of claims; (2) nature of the invention; (3) state of the prior art; (4) 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) quantity of experimentation needed to make or use the invention based on the content of the disclosure; and (8) Predictability of the art.
(1) Breadth of claims
This factor weighs against enablement.
Claim 1 is not limited to acute ischemic stroke, cerebral anterior circulation infarction, non-cardiogenic infarction, a particular NIHSS range, a particular agent group, or treatment within a specified period following stroke onset. Indeed, claim 1 encompasses prevention or treatment of the broader genus of cardio-cerebral ischemic disease or cardio-cerebral circulation disorder using BZP.
The dependent claims primarily narrow dosage, dosing frequency, route of administration, dosage form, or treatment outcome. Those limitations do not necessarily restric the underlying disease in claim 1 to the experimentally supported acute ischemic stroke embodiments. Thus, the scope sought is materially broader than the disease conditions for which the specification provides its substantive experimental guidance.
(2) Nature of the invention
This factor also weighs against enablement of the full scope.
The claimed invention concerns the therapeutic use of a pharmaceutical compound to prevent or treat a broad class of ischemic disorders. Whether a pharmaceutical intervention produces a therapeutically effective result depends upon biological and clinical variables including the affected tissues and vascular, etiology, and mechanism of the ischemic condition, disease severity, timing of intervention, dose, route of administration, and characteristics of the treated patient population.
Accordingly, efficacy established for a particular acute ischemic stroke population does not, without additional evidence of technical guidance, necessarily establish therapeutic efficacy across the entire genus of cardio-cerebral ischemic diseases encompassed by claim 1.
(3) State of the prior art
The prior art provides evidence supporting activity of the class compounds in cerebral ischemia/acute ischemic stroke, but does not establish predictable efficacy throughout the full cardio-cerebral ischemic disease genus.
Gubskiy et al. (Original Article, Open access, published: 25 November 2017, Volume 9, pages 417–425, (2018) teach that the MCAO model closely imitates acute ischemic stroke. Thus, the relevant prior-art evidence provides additional support for activity in an acute cerebral ischemia/stroke setting, but does not establish that such activity can predictably be extrapolated to every cerebral ischemic disease encompassed by claim 1.
Likewise, Chang’s experimental evidence is directed to cerebral ischemia. Chang evaluates the compounds using an MCAO cerebral ischemia/reperfusion model and reports reduction of cerebral infarct size, including favorable activity of the 5-bromo compound. See Embodiment 10, pp. 10-21).
The prior art therefore reinforces the disclosed activity in cerebral ischemia/AIS but does not provide the missing guidance necessary to practice the claimed treatment and prevention throughout the broader disease genus.
(4) Level of one of ordinary skill in the art
This factor weighs against enablement.
Therapeutic efficacy across different ischemic disorders is not reasonably established merely because efficacy has been demonstrated in a particular acute ischemic stroke setting.
Indeed, the specification itself employs particular patient-selection criteria, disease severity, timing relative to stroke onset, dosing condition, and outcome measurement in establishing the disclosed clinical effect. These variables demonstrate that therapeutic efficacy is dependent upon more than merely administering BZP to any patient having any condition falling within the broad category cardio-cerebral ischemic disease or cardio-cerebral circulation disorder.
Accordingly, extrapolation throughout the claimed genus would not have been reasonably predictable based upon the disclosure presently claimed.
(5) Amount of direction or guidance provided by the inventor
This factor weighs against enablement of the full scope.
The specification provides meaningful guidance concerning acute ischemic stroke and therefore the Examiner does not rely upon an assertion that the specification fails to teach how to use BZP at all. Rather, the deficiency concerns the absence of sufficient guidance for extending the disclosed therapeutic methodology beyond the exemplified acute ischemic stroke context throughout the full genus encompassed by claim 1.
The specification does not provide sufficient disease -specific guidance identifying for the other encompassed cardio-cerebral ischemic disease or cardio-cerebral circulation disorder, which patient populations should be treated, appropriate therapeutic window, whether prevention vs therapeutic administration is effective, or whether the disclosed dosage conditions would reasonably produce the claimed therapeutic effect.
(6) Existence of working examples
This factor weighs against enablement of the full claimed scope, although working examples are present.
Applicant has provided experimental evidence concerning BZP and acute ischemic stroke. Those examples are relevant and are acknowledged. The deficiency is therefore not an absence of working examples. Rather, the working examples occupy a substantially narrower portion of the disease genus encompassed by claim. The examples do not establish a demonstrated therapeutic effect across the remaining cardio-cerebral ischemic disease or cardio-cerebral circulation disorder encompassed by the claim.
For comparison, Chang likewise reports specific MCAO rat cerebral-ischemia model rather than experimental demonstration across every broadly stated cardio-cerebral ischemic disease or cardio-cerebral circulation indication. See pp. 19-21, Embodiment 10.
(7) Quantity of experimentation needed to make or use the invention based on the content of the disclosure
This factor weighs against enablement.
To practice the claimed invention throughout its full scope, the skilled artisan would need to determine, for materially different cardio-cerebral ischemic disease or cardio-cerebral circulation disorder, whether BZP provides an effective therapeutic or preventive benefit and, where appropriate, establish suitable patient populations, treatment timing, dose and administration conditions.
Such experimentation would not merely involve routine optimization of a known effective treatment within a narrow parameter range. Rather, for disease embodiments outside the demonstrated acute ischemic stroke context, experimentation would first be necessary to establish that the claimed therapeutic intervention is effective for the particular disease itself.
(8) Predictability of the art
This favor weighs significantly against enablement of the full scope claimed.
Bath et al. (Int J Stroke. 2015 Mar 2;10(4):469–478) established therapeutic strategies were lacking for prevention or treatment of cerebral small vessel disease, notwithstanding emerging information concerning potential useful approaches. (See Conclusions).
This evidence demonstrates that ischemic cerebrovascular disorders falling within the broad terminology employed by claim 1 do not necessarily share a single predictable therapeutic response merely because a compound demonstrates efficacy in acute ischemic stroke.
Further evidence of the unpredictability associated with extrapolating therapeutic efficacy across the breadth of the claimed disease genus is provided by Gao et al. (Front Cardiovasc Med. 2025 Mar 25; 12:1507665 pages 1-10). Although Gao postdates the effective filing date of the instant application, a post-filing factual reference may be relied upon where it provides evidence that, as of the application’s filing date, undue experimentation would have been required to practice the claimed invention throughout tis scope. See MPEP §2124, in re Corneil, 347 F.2d 563, 568 (CCPA); see also Amgen Inc v. Sanofi, 872 F.3d 1367, 1375 (Fed. Cir. 2017).
Gao et al. describes cardio-cerebral infarction as involving a range of complex pathophysiological mechanisms, including atherosclerosis, neurogenic factors, inflammation, cardiac factors, and systemic diseases, and further describes continuing challenges associated with classification, diagnosis, and treatment. (Conclusion, first paragraph).
Gao is not relied upon to establish a post-filling state of the art or impose subsequently developed knowledge upon the disclosure. Rather, Gao provides factual evidence corroborating the biological and clinical heterogeneity of the disease conditions encompassed by the broadly claimed cardio-cerebral ischemic disease genus and the resulting experimentation necessary to determine whether therapeutic efficacy demonstrated to BZP in acute ischemic stroke can be extrapolated to materially different disease embodiments. See MPEP §2124.
Conclusion
Considering the relevant factors together, the specification reasonably enables the disclosed acute ischemic stroke embodiments but does not provide sufficient teaching or representative evidence to enable the full scope of the broader cardio-cerebral ischemic disease” or “cardio-cerebral circulation indication disorder” genus encompassed by claim 1 without undue experimentation.
The rejection is therefore directed to disparity between breadth of the disease genus actually claimed and the substantially narrower therapeutic embodiments for which sufficient enabling guidance is provided. The rejection is not based merely upon the absence or an example for every embodiment and is not based upon an assertion that therapeutic efficacy must be demonstrated by clinical trials in every instance.
Acknowledgement is made of the receipt and entry of Applicant’s arguments and remarks filed on August 03, 2026.
Applicant’s amendment of claim 6 to require that the disease is acute ischemic stroke is acknowledged and is persuasive with to the scope of claim 6 and claims depending therefrom. Accordingly, claim 6 and claims depending therefrom that remail limited to acute ischemic stroke are not included in the present enablement.
However, the amendment to claim 6 does not overcome the rejection of independent claim 1 or claims depending from claim 1 that are not limited through claim 6. Claim 1 continues to recite preventing or treating “a cardo-cerebral ischemic disease” and therefore remains generic to the different cardio-cerebral ischemic disease encompassed by the terminology. The amendment of the plural “disease” to the singular “a …. disease” does not restrict claim to acute ischemic stroke.
As set forth in the rejection above, the Examiner acknowledges that specification provides enabling guidance for the disclosed acute ischemic stroke embodiments. The deficiency concerns the materially broader disease genus encompassed by claim. The evidence of record, including the stated of the art concerning cerebral ischemia and the recognized unpredictability of treatment across materially different cardiovascular ischemic conditions, establishes a reasonable basis to conclude that the skilled artisan could not extrapolate the AIS teachings throughout the full scope of claim without undue experimentation.
Accordingly, Applicant’s amendment is sufficient to remover the claims limited though to remove the claims limited through claim 6 from the scope of the enablement rejection but does not overcome the rejection of claims that continue to encompass the broader cardio-cerebral ischemic disease genus.
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 remain 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.
Acknowledgement is made of the receipt and entry of Applicant’s arguments and remarks filed on August 03, 2026.
Applicant argue that Chang does not disclose sodium 5-bromo-2-(α-hydroxypentyl) benzoate (BZP) because Chang’s generic formula encompasses numerous possible combinations and because the biological examples identify potassium -5-lfuoro- and potassium 5-bromo-2-(α-hydroxypentyl) benzoate rather than the presently claimed sodium BZP species.
Applicant’s argument has been fully considered but is not persuasive. Anticipation of a chemical species does not require that the prior art reference reproduce the complete name of the claimed species in a single sentence or working example. A generic example disclosure sufficiently identifies the species such that one of ordinary skill would at once envisage the claimed species from the disclosed alternatives. See MPEP §2131.02.
Here, Chang does not merely disclose an undifferentiated genus. Chang expressly identifies sodium as one of the metal ions M for the disclosed halogenated -2-(α-hydroxypentyl)benzoate (see claims 1-2, pp. 2-3), actually prepares a sodium salt of the disclosed halogenated class in embodiment 2 (see p. 15), and specifically identifies and biologically evaluates the 5-bomo species as one of the particularly active members of the class (See pp. 19-21, Embodiment 10).
Accordingly, when Chang is considered as a whole rather that limiting its disclosure to the particular potassium salt employed in one biological example, sodium 5-bromo-2-(α-hydroxypentyl) benzoate is directly envisaged from Chang’s expressly delineated alternatives.
Applicant further argues that Chang’s dosage disclosure concerns the generic halogenated class rather than the specific claimed BZP species.
In response, this argument is not persuasive. One of the claimed sodium 5-bromo species is recognized as an anticipated species within Chang’s disclosure, Chang’s therapeutic and dosage teachings apply to the disclosed class containing that species. Chang expressly teaches a daily dose of 200-600 mg, preferably 100 mg, which may be administered once or several times. (See p. 14.) The expressly preferred 100 mg daily dose falls within claim1’s 50-500 mg range and is expressly recited as one of the alternatives in claim2. A specific prior-art value falling within a claimed range anticipates that range. MEPE §2131.03(I).
Accordingly, Applicant’s arguments do not overcome the anticipation rejection of claims 1-2, 10, and 12-13.
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 remain rejected and claims 26-29 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.
With respect to claim 26, which depends from claim 2 and requires an administered daily dose of BZP of 400 mg, Chang teaches administration of 200-600 mg per day, halogenated 2-(α-hydroxyl pentyl) benzoate, production method. See page 14. The specifically recited 400-mg daily dose therefore falls squarely within the daily dosage range taught by Chang.
With respect to claim 27, which depends from claim 3 and recites particular single doses including 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. Chang teaches a daily dose of 200-600 mg and further teaches that the daily amount may be administered once or several times, halogenated 2-(α-hydroxyl pentyl) benzoate, production method. See p. 14. Thus, where Chang’s daily amount is administered once, Chang teaches or suggests single doses falling within the alternatives recited in claim 27.
With respect to claim 28, which depends from claim 27 and requires a single dose of 200 mg BZP, Chang teaches a daily dosage beginning at 200 mg and expressly provides that the daily amount may be administered once, halogenated 2-(α-hydroxyl pentyl) benzoate, production method. See p. 14. Accordingly, administration of the 200 mg daily amount in a single administration would have resulted in the present recited 200-mg single dose.
With respect to the claimed presently designated claim 29 that depends from claim 4, the claim requires administration of BZP twice a day. Chang expressly teaches that the daily dose may be administered “once or several times”, halogenated 2-(α-hydroxy pentyl) benzoate, and production method. Selection of twice-daily administration from Chang’s expressly disclosed multiple daily administration would have been an obvious selection of a dosing frequency within Chang’s teaching, particularly where the total daily dose remains within the disclosed daily dose range.
With respect to claim presently designated claim 29 that depends from claim 6, the claim further requires that the acute ischemic stroke. Rehani teaches the use of neurological severity, including NIHSS, in the selection and treatment of acute ischemic stroke patients and reports favorable treatment outcomes in patients having moderate NIHSS scores. See pa 32, “Use of NIHSS score for intervention Criteria”).
It would have been obvious to apply the ischemic stroke treatment previously set forth in the rejection to mild or moderate acute ischemic stroke patients, which constitute recognized severity categories of the same disease being treated.
Acknowledgement is made of the receipt and entry of Applicant’s arguments and remarks filed on August 03, 2026.
Applicant argues that Chang does not disclose the presently claimed sodium 5-
bromo-2-(α-hydroxyl pentyl) benzoate (BZP) because Chang generically defines R1, n, and M and allegedly directs the skilled artisan toward the potassium 5-fluoro and potassium 5-bromo compounds rather than the presently claimed sodium BZP.
In response, Applicant’s argument has been considered and are not persuasive. Chang expressly teaches that M may be a monovalent metal ion and specifically identifies sodium ion as one of the preferred ions. (p. 3, claim 1-2.) Chang further actually prepares a halogenated 2-(α-hydroxypenty) benzoic acid sodium salt in Embodiment 2, p. 15. Chang separately identifies the 5-bromo compound as one of its particularly effective compounds in the cerebral ischemia model. Specifically, Chang reports that 5-fluro- and 5-bromo-2-(α-hydroxypenhyl) benzoate potassium salts provided favorable reductions in cerebral infarct size (p. 21, Experimental Results and Conclusions). Thus, while Chang’s experimental 5-bromo species employes potassium rather sodium, Chang expressly teaches both the 5-bromo substitution and sodium salts within the same disclosed class.
More importantly, Tian expressly identifies the precise species at issue. “brozopentyl sodium salt, sodium (+/-)-5-bromo-2-(α-hydroxypenyl) benzoate (BZP),” and teaches that this compound is a novel agent showing promising outcomes for treatment of ischemic stroke. See p. 1, introduction, last paragraph. Tian further reports that BZP reduced cerebral infarction volume in focal cerebral ischemia-reperfusion injury, prevented permanent global brain ischemia, and was more active and secure than Br-NBP. See p. 2, Introduction.
Accordingly, the obviousness rejection does not require the skilled artisan to arrive at the claimed compound through hindsight selection from Chang’s genus. Tian expressly identifies the exact claimed sodium BZP compound and expressly associates that compound with treatment of ischemic stroke. Chang further provides the pertinent therapeutic, dosage, divided administration, and formulation teachings.
Applicant argues that neither Tian nor Rehani teaches the limitation that “the daily
dose of BZP is 50-500 mg.”
In response, this argument is not persuasive because the rejection does rely upon Tian or Rehani for the claimed daily dosage. Chang expressly teaches that the amount administered may vary according to the route of administration, patient age and weight, and type and severity of disease, and teaches a daily dosage of 200-600 mg which may be administered once or in several portions. See p.14.
Change disclosed 200-600 mg/day range therefor overlaps the claimed 50-500 gm/day. The cited references need not individually disclose every limitation where the rejection is based upon their combined teachings.
Tian is relied upon principally for its express identification of the exact claimed BZP species and its known anti-ischemic-stroke activity, while Rehani provides additional teachings concerning human acute ischemic stroke and clinically recognized treatment windows and patient-selection considerations.
Accordingly, the absence of a BZP daily-dose teaching in Tian or Rehani individually does not overcome the rejection.
Applicant further relies upon clinical trial results in which patient with acute
ischemic stroke received 200 mg BZP twice daily by intravenous infusion for 14 consecutive days and argues that the results corroborate the technical effects achieved by the claimed dosing regimen.
In response, the evidence has been considered and is probative of the tested embodiment. However, it is insufficient to overcome the prima facie case of obviousness.
First, the tested regimen falls within the dosing teaching of the prior art. Administration of 200 mg twice daily corresponds to 400 mg/day. Chang expressly teaches 200-600 mg/da and further teaches that the daily amount may be administered once or in several portions. Thus, the evidence concerns a dosage amount and divided administration regimen falling within the scope suggested by the prior art.
Second, the results presented by Applicant do not establish a statistically significant unexpected improvement over the control. Applicant reports that the proportion of subjects achieving an mRS score of 0-1 at day 90 was 61.0% (64/102) for the 200-mg BZP group compared with 51.4% (57/111) for placebo, corresponding to a difference of 9.6%. However, Applicant’s own disclosure report 95% confidence interval of -3.6% to 22.8% and P = 0.155 for the exploratory comparison. Thus, while the numerical results favors the BZP treated groups, the submitted evidence does not establish that the observed difference represents a statistically significant improvement attributable to the claimed regimen.
Third, the prior art already provided reason to expect therapeutic activity from the claimed compound. Tian expressly characterizes BZP as showing promising outcomes for ischemic stroke and reports prior evidence that BZP reduces cerebral infarction volume in focal cerebral ischemia-reperfusion injury. Thus, evidence showing therapeutic activity of BZP in acute ischemic stroke is consistent with, rather than contrary to, the therapeutic activity suggested by the prior art.
Moreover, Rehani identifies improvement in functional outcome measure by mRS at 90 days as a recognized outcome of acute ischemic stroke treatment and reports favorable functional outcomes in established stroke-intervention studies. See p. 31, “Outcome Measures”).
Accordingly, Applicant’s evidence demonstrates therapeutic activity for the particular 200-mg twice daily regimen tested, but does not establish that the observed result was unexpected relative to what the prior art would have led one of ordinary skill to expect.
To the extent Applicant relies upon the clinical evidence to support claim 11, the
argument is likewise not persuasive.
Claim 11 depends from claim 5 and therefore requires the 200 -mg twice daily BZP regimen. The further recitation that the dosage regimen “has a lower incidence of adverse effects than other dosage regimens and achieves better improved effects than other dosage regimens” characterizes the results or properties attributed to the positively recited dosage regimen rather than reciting a separate method step.
As discussed above, the 200-mg twice daily regimen provides a total daily dosage of 400 mg, falling within Chang’s disclosed 200-600 mg/day range, and Chang expressly permits the daily dosage to be administered in multiple portions.
Furthermore, the submitted clinical evidence compares the 200-mg BZP regimen principally against placebo for the identified mRS outcome. Such a comparison does not, by itself, establish the limitation of claim 11 requiring a lower incidence of adverse events “than other dosage regimens” and better improved effects “than other dosage regimens.” Establishing the comparative limitation would require evidence permitting a meaningful comparison of the claimed 200 -mg twice daily regiment with relevant alternative BZP dosage regimens.
Accordingly, the submitted evidence does not establish that the particular safety and efficacy characteristics recited in claim 11 constitute an unexpected property sufficient to outweigh the prima facie case of obviousness.
Conclusion
Claims 1-13 and 26-29 are not allowed.
THIS ACTION IS MADE FINAL. 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.
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/JEAN P CORNET/ Primary Examiner, Art Unit 1628
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