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 .
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 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.
DETAILED ACTION
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on Dec. 1, 2025 has been entered. All arguments and the IDS submitted on Dec. 1, 2025 have been fully considered.
Status of the Claims
Claims 23, 25-35, and 37-45 are pending.
Claim 23 is amended.
Claims 1-22, 24 and 36 are cancelled.
New claims 43-35 have been added.
Claims 23, 25-35, and 37-45 have been considered on the merits.
Claim Objections
New claim objections have been added due to amendment.
The disclosure is objected to because of the following informalities:
Claims 23, 43, and 44 are objected to in the recitation of “wherein the aptamer is administered to the subject before 12 hours after performing the artery recanalization”, and in the interest of improving claim form, it is suggested that the recited phrase be amended to recite “and wherein the aptamer is administered to the subject before 12 hours after performing the artery recanalization”.
Appropriate correction is appreciated.
Claim Rejections - 35 USC § 112
New claim rejections under 35 USC § 112, (b) or second paragraph (pre-AIA ) have been added to address the claim amendments.
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 23, 25-35, and 37-45 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.
In claims 23, 43 and 44, the phrase “wherein the aptamer is administered to the subject before 12 hours after performing the artery recanalization”, renders the claim and its dependents indefinite, since it is unclear exactly time frame this phrase is meant to encompass for the administration of the aptamer. For instance, the phrase could mean that the aptamer is administer any time prior to 12 hours after artery recanalization is performed which would include administration of the aptamer before artery recanalization and concurrently with artery recanalization. Alternatively, the phrase would mean that the aptamer is administer within 12 hours after artery recanalization and exclude the time period prior and concurrently with artery recanalization. For the purposes of compact prosecution, the phrase will be interpreted to mean that aptamers may be administered any time proceeding 12 hours after artery recanalization including before and concurrently with artery recanalization. This is based on dependent claims 29 and 31-33 which limit the administration of the aptamer to prior to artery recanalization.
All other claims depend directly or indirectly from rejected claims and are, therefore, also rejected under USC 112 for the reasons set forth above.
Appropriate correction is appreciated.
Claim Rejections - 35 USC § 103
The claim rejections under 35 USC § 103 are withdrawn due to amendment. New claim rejections under 35 USC § 103 have been added to address the claim amendments.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 23, 25-35, and 37-45 are rejected under 35 U.S.C. 103 as being unpatentable over Lizasoain Hernandez et al. (US 2017/0130227 A1) (ref. of record) as evidenced by Struys et al. (Anesthesia & Analgesia, 2016) (ref. of record) in view of Zhang et al. (US 2022/0000932 A1, priority to Sept. 28, 2018) (ref. of record).
With respect to step (ii) of claims 23, 43, and 44, Lizasoain Hernandez teaches a method of treating ischemic stroke due to sudden and immediate interruption of blood flow (acute) by administering an aptamer that binds specifically to and inhibits TLR-4 (abstract, 0001, 0017-0018, 0029, 0159-0160).
With respect to claims 23, and 43-45, Lizasoain Hernandez teaches aptamers with 100% homology to the claimed aptamers (0008, 0030, 0035 and 0052). Specifically, Lizasoain Hernandez teaches an aptamer with SEQ ID NO. 1 (TLRApt#1R-T) that has 100% homology with claimed SEQ ID NO. 2, an aptamer with SEQ ID NO. 2 (TLRApt#4F-T) that has 100% homology with claimed SEQ ID NO. 1 or ApTOLL, an aptamer with SEQ ID NO. 3 (TLRApt#1R) that has 100% homology with claimed SEQ ID NO. 3, and an aptamer with SEQ ID NO. 4 (TLRApt#4F) that has 100% homology with claimed SEQ ID NO. 4. With respect to step (i) of claims 23, 43, and 44, and claims 27 and 28, Lizasoain Hernandez teaches the method where tissue plasminogen activator is co-administered with the aptamer (0194). Therefore, pharmacological recanalization and pharmacological thrombolysis would occur concurrently with the administration of the aptamer and before 12 hours after artery recanalization has occurred (0073 and 0194).
Lizasoain Hernandez teaches the method for improving the therapeutic outcome of treating stroke (0029). Lizasoain Hernandez does not explicitly teach the method for improving the therapeutic outcome of artery recanalization as recited in the preambles claims 23, 43 and 44. The preambles recite intended results of the method rather than requiring an additional step be performed. MPEP 2111.04 states “Claim scope is not limited by claim language that suggests or makes optional but does not require steps to be performed” and that a such a clause ‘"in a method claim is not given weight when it simply expresses the intended result of a process step positively recited.” Therefore since these claims only recite the results of the steps, then art reading on claimed method of administering an aptamer that binds specifically to and inhibits TLR-4 to a subject with an acute ischemic stroke and performing artery recanalization on the subject will also read on these results since performing the same steps will inherently lead to the same results in the absence of evidence to the contrary including unexpected results. Furthermore, it is noted that Lizasoain Hernandez teaches the method where the infarcted area in an animal model of stroke is reduced (0249 and 0255) and where pro-inflammatory cytokines are reduced, including IL-1, IL-8, TNF-alpha and IL-12 following administering an aptamer that binds specifically to and inhibits TLR-4 and co-administration of a tissue plasminogen activator (pharmacological recanalization and pharmacological thrombolysis) (0105, 0151, and 194). Therefore, there is improved therapeutic outcome.
With respect to claim 34, Lizasoain Hernandez teaches the pharmaceutical compositions can be delivered intravenously and by transfusion (0207).
Lizasoain Hernandez is silent with how long the duration of the infusion of the aptamer is and does not teach the infusion has a duration of about 5, 10, 15, 20, 25 or 30 minutes as recited in claim 35. However, one of ordinary skill in the art would recognize that the duration of an infusion of a pharmaceutical composition into a subject is a result effective variable and that the duration of the infusion would be matter of routine optimization as evidenced by Struys. Struys teaches determining the infusion rate for IV drug depends on factors such as the predicted drug concentration at the tissue of interest and maintaining a stable concentration in the plasma or tissue (abstract, pg. 65 para. 1-2 and Fig. 1).
With respect to claims 37 and 38, Lizasoain Hernandez teaches daily doses in the range of 0.0001 to 1.000 mg/kg of body weight (0212). Lizasoain Hernandez further teaches the unit dosage of the composition of aptamers delivered depends on the features of the active compound, the particular therapeutic effect to be achieved and what is suitable for the subject to be treated (0211). Although Lizasoain Hernandez does not teach the exact range of 0.007 to 0.2 mg/kg of body weight as claim 38, the ranges overlap significantly with the ranges taught. Even though Lizasoain Hernandez is silent with respect to amount of aptamer per dose and does not teach a dose range of 0.5 to 14 mg/dose as recited in claim 37, one of ordinary skill in the art would recognize that the dose administered to a subject is a result effective variable and that the dose would be matter of routine optimization as evidenced by Lizasoain Hernandez.
With respect to claim 39, Lizasoain Hernandez teaches the method where aptamer is formulated in phosphate buffer saline (PBS) with magnesium chloride (0025, 0142, 0208, 0226 and 0249). PBS has a pH of 7.4. It is noted the claim recites that A-trehalose dihydrate can be optionally included in the formulation and the term “optionally” does not require that A-trehalose dihydrate be included in the formulation.
Claims 40-42 contain wherein clauses that recites intended results of the method rather than requiring an additional step be performed. MPEP 2111.04 states “Claim scope is not limited by claim language that suggests or makes optional but does not require steps to be performed” and that a such a clause ‘"in a method claim is not given weight when it simply expresses the intended result of a process step positively recited.” Therefore since these claims only recite the results of the steps, then art reading on claimed method of administering an aptamer to a subject with an acute ischemic stroke will also read on these results since performing the same steps will inherently lead to the same results in the absence of evidence to the contrary including unexpected results. Furthermore, it is noted that Lizasoain Hernandez teaches the method where the infarcted area in an animal model of stroke is reduced (0249 and 0255) and where pro-inflammatory cytokines are reduced, including IL-1, IL-8, TNF-alpha and IL-12 (0105 and 0151).
Lizasoain does not explicitly teach the method where the subject is undergoing artery recanalization as recited in claim 23. Lizasoain Hernandez does not teach the method where the artery recanalization is mechanical as recited in claims 23, 43 and 44, where the mechanical artery recanalization is endovascular thrombectomy as recited in claim 25, or where the endovascular thrombectomy is stent-retriever thrombectomy, balloon embolectomy, direct aspiration thrombectomy, surgical embolectomy or a combination of thereof as recited in claim 26.
However, Zhang teaches a similar method where a therapeutic composition is administered to a subject who has had an ischemic stroke and is undergoing artery recanalization (abstract and 0028). Zhang teaches balloons and stents are used to recanalize arteries when clot removal or dissolution was not possible (0007 and 0049) and teaches thrombectomy can be performed with a stent-retriever, a balloon maceration device (balloon embolectomy), and an aspiration device (direct aspiration thrombectomy) (0049 and 0270).
Accordingly, at the effective time of filing of the claimed invention, one of ordinary skill in the art would have been motivated to modify the method of Lizasoain Hernandez to include patients undergoing artery recanalization and to include mechanical artery recanalization including the claimed endovascular thrombectomy methods for the benefit of being able to recanalize arteries when clot removal or dissolution methods are not possible as taught by Zhang. It would have been obvious to one of ordinary skill in the art to modify the method of Lizasoain Hernandez to use alternate known methods of recanalizing arteries in ischemic stroke patients such as mechanical artery recanalization including the claimed endovascular thrombectomy methods as taught by Zhang. A person of ordinary skilled in the art would have been motivated to do so because Zhang teaches a similar method where a therapeutic composition is administered to a subject who has had an ischemic stroke along with artery recanalization. Since these methods of artery recanalization for ischemic stroke patients were known in the art for the same purpose of treating acute ischemic stroke as taught by Zhang, one of ordinary skill in the art would have had a reasonable expectation of success in including these methods in the method of Lizasoain Hernandez. Furthermore, it would have been obvious to a person skilled in the art to combine other known treatments including mechanical artery recanalization and subjects undergoing artery recanalization as taught by Zhang along with the aptamers to TLR-4 taught by Lizasoain Hernandez with a reasonable expectation of success.
Similarly, Lizasoain Hernandez does not teach the method where the aptamer is administered prior or immediately after artery recanalization as recited in claim 29, where it is administered at least 10 min after artery recanalization as recited in claim 30, where it is administered at least 30 min prior to artery recanalization as recited in claim 31, where it is administered prior and immediately after artery recanalization as recited in claim 32, or where it is administered at least 30 min prior to artery recanalization and about 10 min after artery recanalization as recited in claim 33.
However, Zhang teaches a similar method where a therapeutic composition is administered to a subject who has had an ischemic stroke (0028). Zhang teaches the therapeutic composition (mammalian exosomes) can be administered concomitantly or sequentially (prior or subsequently) with the thrombectomy that is performed (0050-0057). Zhang teaches the method where the therapeutic composition is administered prior to the thrombectomy procedure and then afterwards in one more doses hourly, daily, weekly or monthly (0221). Zhang teaches the quantity of the therapeutic composition (mammalian exosomes) administered and the timing of administration may vary for the patient being treated (0214-0215). Zhang further teaches that the dosage regimens for the therapeutic composition (mammalian exosomes) and iPA and/or thrombectomy procedure may be adjusted for the optimum therapeutic response depending on the situation and will depend on many factors including the subject’s age, gender, weight and physical condition, the severity of the symptoms, duration of the treatment, and the carrier being used (0276). Zhang teaches that dosages for a particular patient can be determined by one of ordinary skill in the art using conventional considerations (0206). In addition, Zhang teaches that the timeframe for effective treatment of stroke is within 3 hours for intravenous (IV) thrombolytic therapy and within 24 hours for site-directed intra-arterial thrombolytic therapy or interventional recanalization of a blocked cerebral artery (0005). Zhang further teaches that there is strong evidence that the shorter the time period between onset of symptoms and treatment the better the results (0005).
Accordingly, at the effective time of filing of the claimed invention, one of ordinary skill in the art would have been motivated to modify the method of Lizasoain Hernandez so that the aptamer is delivered either before, after, or before and after artery recanalization for the benefit of being able to provide the appropriate timing of the aptamer during the therapy recanalization as suggested by Zhang. It would have been obvious to one of ordinary skill in the art to modify the method of Lizasoain Hernandez to use different timings of delivering the aptamer based on the recanalizing arteries in ischemic stroke patients, since adjusting the delivery time of pharmaceuticals around the artery recanalization was known in the art as taught by Zhang. Since the administration of pharmaceuticals to aid stroke patients was known to be performed before and after artery recanalization as taught by Zhang, one of ordinary skill in the art would have had a reasonable expectation of success modifying the method of Lizasoain Hernandez so that the aptamer is delivered either before, after, or before and after artery recanalization as claimed. Although Zhang does teach the exact times of when the aptamer is administered as recited in claims 23, 30, 31, 33, 43 and 44, one of ordinary skill in the art would recognize that the time of delivery of a pharmaceutical composition into a ischemic stroke subject is a result effective variable and that the time of delivery of a pharmaceutical composition would be matter of routine optimization as evidenced by Zhang. Zhang teaches that dosage regimen for a particular patient can be determined by one of ordinary skill in the art using conventional considerations (0206, 0214-0215, and 0276). Furthermore, even though the timeframe that Zhang references is not explicitly to the artery recanalization procedures, it would be obvious to one of ordinary skill the art that additional treatments would also provide maximum effectiveness within the claimed shorter timeframes which would be closer to the onset of the stroke and closer to the time of the artery recanalization procedure.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective time of filing of the invention, especially in the absence of evidence to the contrary.
Response to Arguments
Applicant's arguments filed Dec. 1, 2025 have been fully considered but they are not persuasive.
With respect to the rejections under 35 U.S.C. § 103, Applicant argues that the combined teachings of Lizasoain Hernandez and Zhang does not teach a method of improving therapeutic outcome of artery recanalization in a subject following an acute ischemic stroke that comprises a step of administering an aptamer before 12 hours after performing the artery recanalization (Remarks pg. 6 para. 4 to pg. 7 para. 1 and pg. 8 para. 2). The Applicant’s amendments limiting claim 23 to include these new limitations necessitated new rejections. Applicant’s arguments are drawn to Lizasoain Hernandez and Zhang failing to teach these new limitations. However, the new limitations are addressed in the new rejections.
Applicant argues that one of ordinary skill in the art would not have arrived at the claims by routine optimization, since Zhang does not teach optimizing the time of delivery of administering miRNA compositions even though they teach the miRNA may be administered before or after tPA administration or thrombectomy (Remarks pg. 7 para. 2). However, this argument was not found to be persuasive, since Zhang teaches optimizing the timing and dosage of the therapeutic composition. In addition, Zhang teaches that the timeframe for effective treatment of stroke is within 3 hours for intravenous (IV) thrombolytic therapy and within 24 hours for site-directed intra-arterial thrombolytic therapy or interventional recanalization of a blocked cerebral artery (0005). Zhang further teaches that there is strong evidence that the shorter the time period between onset of symptoms and treatment the better the results (0005). Although the timeframe that is reference in the claims is to the artery recanalization procedures, it would be obvious to one of ordinary skill the art that additional treatments would also provide maximum effectiveness within these shorter timeframes that are closer to the onset of the stroke and closer to the time of the artery recanalization procedure.
Applicant argues that there are secondary considerations, or unexpected results, that support the nonobviousness of the claims. Specifically, Applicant argues that the results described in Example 2 and pg. 9-10 and 96 of the instant specification demonstrate that there is an improved therapeutic outcome when the aptamer is administered before 12 hours after performing the artery recanalization (Remarks pg. 7-8 bridging para. and pg. 8 para. 2). Although the data clearly shows when a 0.45 mg/kg dose of ApTOLL was administered to a rat stroke model either 30 min. before reperfusion, or at 10 min, 2 hrs, 6 hrs, or 12 hrs after reperfusion there was a protective effect compared to when the aptamer was administered 24 hrs after reperfusion (0442 of published application), the data is not commensurate in scope with the claim invention. The claimed method is broader for the amount dose of the aptamer that may be used than the method for generating the data in the specification. Specifically, the claimed method includes any dose of the aptamer which binds and inhibits TLR-4 which would include doses that do not have any effect. Additionally, the specification discloses that only when either a 0.91 mg/kg dose or a 0.45 mg/kg dose of the aptamer, ApTOLL, was administered to a rat stroke model there was a protective effect, but the other doses tested in the dose range of 0.009 mg/kg to 9 mg/kg did not produce a significant protective effect (0430-0431 of published application). Further, the claims require artery recanalization, which is not performed in the method in Example 2. Therefore, it is unclear if the same effects would be achieved under the conditions recited in the claims.
Conclusion
No claims are allowed.
Examiner Contact Information
Any inquiry concerning this communication or earlier communications from the examiner should be directed to EMILY ANN CORDAS whose telephone number is (571)272-2905. The examiner can normally be reached on M-F 9:00-5:30 EST.
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/EMILY A CORDAS/Primary Examiner, Art Unit 1632