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 .
DETAILED ACTION
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.
Response to Amendments
Applicant’s amendments, amendments to specification, IDSs, and response filed May 27, 2026 have been received and entered into the case.
Status of the Claims
Claims 23, 25-35, 37, 39-43,and 46-49 are pending.
Claims 23, 25, 27, 37 and 43 are amended.
Claims 1-22, 24, 36, 38 and 44-45 are cancelled.
Claims 46-49 are new.
Claims 23, 25-35, 37, 39-43,and 46-49 have been considered on the merits.
Claim Objections
The claim objections have been added due to amendment.
Claim Rejections - 35 USC § 112
The claim rejections under 35 USC § 112, (b) or second paragraph (pre-AIA ), are withdrawn due to amendment. 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, 37, 39-43,and 46-49 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.
Claims 23 and 43 recites the phrase “at least about” renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claim invention. The limitation “at least” implies a lower bound, in this case 0.2 mg/kg, while the limitation “about” implies no distinct lower bound to the 0.2 mg/kg. Therefore, the phrase “at least about” contradicts the range around 0.2 mg/kg which is implied by the claim. Appropriate correction, such as deletion of the term “at least” or the deletion of “about”, is respectfully requested. The claim will be interpreted to mean “at least 0.2 mg/kg”.
In claim 47, the phrase “the method of claim 46, further comprising performing the artery recanalization on the human subject after administering the single-stranded nucleic acid, wherein the artery recanalization is endovascular thrombectomy”, renders the claim and its dependents indefinite, since it is unclear whether endovascular thrombectomy is performed in addition to intravenous thrombolysis which is performed in claim 46 or whether endovascular thrombectomy is performed instead of intravenous thrombolysis. Additionally, claim 47 with respect to claim 46 could mean performing a first artery recanalization by, then administering of the single-stranded nucleic acid, followed by a second artery recanalization by endovascular thrombectomy. For the purposes of compact prosecution, the phrase will be interpreted to mean “the method of claim 46, further comprising performing a second artery recanalization on the human subject after administering the single-stranded nucleic acid, wherein the second artery recanalization is endovascular thrombectomy”.
Similarly, in claim 48, the phrase “optionally wherein the method further comprises performing the artery recanalization on the human subject after administering the single-stranded nucleic acid, wherein the artery recanalization is endovascular thrombectomy”, renders the claim and its dependents indefinite, since it is unclear whether endovascular thrombectomy is performed in addition to intravenous thrombolysis which is performed earlier in the claim or whether endovascular thrombectomy is performed instead of intravenous thrombolysis. Additionally, it could mean performing a first artery recanalization by, then administering of the single-stranded nucleic acid, followed by a second artery recanalization by endovascular thrombectomy. For the purposes of compact prosecution, the phrase will be interpreted to mean “optionally wherein the method further comprises performing a second artery recanalization on the human subject after administering the single-stranded nucleic acid, wherein the second artery recanalization is endovascular thrombectomy”.
In claims 29-34, 37, 39-42 and 49, the term "the aptamer" lacks sufficient antecedent basis and renders the claims and their dependents indefinite. For the purposes of compact prosecution, the term will be interpreted to mean to refer to “the single-stranded nucleic acid” recited in claims 23 and 43.
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, 37, 39-43, and 49 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 and 43, Lizasoain Hernandez teaches a method of treating ischemic stroke due to sudden and immediate interruption of blood flow (acute) by administering an aptamer (a single-stranded nucleic acid) that binds specifically to and inhibits TLR-4 to a subject (abstract, 0001, 0017-0018, 0029, 0031, 0159-0160). Further with respect to claims 23 and 43, Lizasoain Hernandez teaches the method where the subject is human (0159).
With respect to claims 23 and 43, Lizasoain Hernandez teaches aptamers with 100% homology to the claimed aptamer (0008, 0030, 0035 and 0052). Specifically, Lizasoain Hernandez teaches an aptamer with SEQ ID NO. 2 (TLRApt#4F-T) that has 100% homology with claimed SEQ ID NO. 1 or ApTOLL.
With respect to step (i) of claims 23 and 43, 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 (0073 and 0194).
Lizasoain Hernandez teaches the method for improving the therapeutic outcome of treating stroke (0029). Although Lizasoain Hernandez teaches the method for improving the therapeutic outcome in a human subject following acute ischemic stroke as recited in the preambles of claims 23 and 43, 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 claims 23, 37, 43 and 49, 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 doses of about 0.2 mg/kg, 0.3 mg/kg, or 0.4 mg/kg as recited in claims 37 and 49 or the range of at least 0.2 mg/kg as claims 23 and 43 are been interpreted as explained in the rejections under 35 U.S.C. § 112 (b), the range taught by Lizasoain Hernandez includes the claimed doses and overlap significantly with the claimed ranges. Furthermore, 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.
Lizasoain Hernandez does not teach the method where the single-stranded nucleic acid or aptamer is administered to the human subject within 12 hours of symptom onset of the acute ischemic stroke as recited in claims 23 and 43.
However, 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 therapeutic aptamer is administered shortly after the symptom onset of the acute ischemic stroke for the benefit of having better treatment results as taught by Zhang. It would have been obvious to a person of ordinary skill in the art to administer the aptamer of Lizasoain Hernandez to patients having an acute ischemic stroke within 12 hours of the symptom onset with a reasonable expectation of success as it is well known in the art to treat such patients as soon as possible as taught by Zhang.
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 claims 35 and 43. 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 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 Hernandez does not teach the method where the artery recanalization is mechanical as recited in claims 23 and 43, 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 an 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.
Claims 46-48 are rejected under 35 U.S.C. 103(a) as being unpatentable over Lizasoain Hernandez as evidenced by Struys and in view of Zhang (as applied to claims 1 above), and further in view of Gerschenfeld et al. (JAMA Neurology, 2017) and Heffernan et al. (US 2011/0293601 A1) (ref. of record).
The teachings of Lizasoain Hernandez and Zhang can be found in the previous rejection above.
Neither Lizasoain Hernandez nor Zhang teach the method wherein the method includes administering the single-stranded nucleic acid to the human subject after performing artery recanalization on the human subject, wherein the artery recanalization is intravenous thrombolysis as recited in claim 46. Lizasoain Hernandez and Zhang do not teach the method further comprising performing a second artery recanalization on the human subject after administering the single-stranded nucleic acid, wherein the second artery recanalization is endovascular thrombectomy as claim 47 is been interpreted as explained in the rejections under 35 U.S.C. § 112 (b). Similarly, Lizasoain Hernandez and Zhang do not teach the method includes administering the single-stranded nucleic acid to the human subject after performing artery recanalization on the human subject, wherein the artery recanalization is intravenous thrombolysis; optionally wherein the method further comprises performing a second artery recanalization on the human subject after administering the single-stranded nucleic acid, wherein the second artery recanalization is endovascular thrombectomy as claim 48 is been interpreted as explained in the rejections under 35 U.S.C. § 112 (b).
However, Gerschenfeld teaches that intravenous thrombolysis (IVT) followed by mechanical thrombectomy (MT) is recommended for treating acute ischemic stroke with a large vessel occlusion (abstract). In addition, Gerschenfeld teaches that intravenous thrombolysis (IVT) given within 4.5 hours of symptom onset has proven efficacy (pg. 550 para. 1).
In further support, Heffernan teaches a method of improving the therapeutic outcome in a subject with an ischemia reperfusion injury where a composition containing a TLR2 modulatory compound is administered to the subject prior to, during or following a surgical procedure including thrombolysis which is performed on a subject prior to, during, or following the occurrence of reperfusion (0011, 0055 and 0092). Heffernan teaches the method where the subject has a reperfusion injury due to a stroke (0004 and 0051). Heffernan teaches TLR2 modulator agent can be an aptamer (0028, 0028 and 0095). In addition, Heffernan teaches the actual dose administered, and the rate and time course of administration of the composition depends on the nature and severity of the condition being treated, such factors such as the age, sex and weight of the patient, the route of administration, and the properties of the composition (0239 and 0242). Heffernan teaches that the dosage regimens can be single or multiple and the compositions can be administered sequential or separately with other therapeutic and medicaments for the treatment of the condition (0240).
Accordingly, at the effective time of filing of the claimed invention, it would have been obvious to a person of ordinary skill in the art to combine other known treatments including a first artery recanalization by intravenous thrombolysis and a second recanalization by endovascular thrombectomy as taught by Gerschenfeld where a therapeutic aptamer is administered following the intravenous thrombolysis as taught by Heffernan. A person of ordinary skill in the art would have been motivated to do so because Gerschenfeld teaches the use of these well-treatments of intravenous thrombolysis and endovascular thrombectomy being combined and Heffernan teaches thrombolysis along with a pharmaceutical therapy for the treatment of acute ischemic stroke. A person of ordinary skill in the art would have recognized that the two recanalization methods along with a therapeutic compound can be also used for the method of using the aptamer taught by the combined teachings of Lizasoain Hernandez and Zhang in treating acute ischemic stroke in a human subject, and combining the two recanalization steps of intravenous thrombolysis and endovascular thrombectomy with an aptamer would be obvious. One of ordinary skill in the art would have had a reasonable expectation of success in making such a modification to the combined teachings of Lizasoain Hernandez and Zhang, since combining performing an artery recanalization with a therapeutic aptamer was known in the art as taught by Lizasoain Hernandez and Heffernan and combining two separate recanalization steps of intravenous thrombolysis and endovascular thrombectomy was known to be effective as taught by Gerschenfeld.
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.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the claims at issue are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); and In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on a nonstatutory double patenting ground provided the reference application or patent either is shown to be commonly owned with this application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The USPTO internet Web site contains terminal disclaimer forms which may be used. Please visit http://www.uspto.gov/forms/. The filing date of the application will determine what form should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to http://www.uspto.gov/patents/process/file/efs/guidance/eTD-info-I.jsp
Claims 23, 25-35, 37, 39-43,and 46-49 are provisionally rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 12-29 of copending Application No. 19/650493. Although the conflicting claims are not identical, they are not patentably distinct from each other because the instant claims encompass those of the copending patent application. In addition, both claim methods of treating a human subject following an acute ischemic stroke by performing artery recanalization and administering a single-strand nucleic acid comprising SEQ ID NO.1
The limitations of the instant claims 23, 29 and 43 are recited by claims 12-15, 27 and 29 of Appl. No. 19/650493.
The limitations of instant claims 30-33, where the single-stranded nucleic acid is administered at least 30 minutes prior to artery recanalization and where the single-stranded nucleic acid is administered at least 10 minutes after artery recanalization and where the single-stranded nucleic acid is administered prior and after performing artery recanalization are recited by claims 16 and 17 of Appl. No. 19/650493.
The limitations of instant claims 25 and 26, where the artery recanalization comprises endovascular thrombectomy, and wherein the endovascular thrombectomy is stent-retriever thrombectomy, balloon embolectomy, direct aspiration thrombectomy, surgical embolectomy, or a combination thereof are recited by claim 18 of Appl. No. 19/650493.
The limitations of instant claims 27 and 28, where the artery recanalization comprises pharmacological thrombolysis or pharmacomechanical thrombolysis, wherein the pharmacological thrombolysis comprises administration of tissue plasminogen activator are recited by claim 19 of Appl. No. 19/650493.
The limitations of instant claims 46-48, where the method comprises administering the single- stranded nucleic acid to the subject after performing artery recanalization on the subject, wherein the artery recanalization is intravenous thrombolysis and further comprising performing a further artery recanalization on the subject after administering the single-stranded nucleic acid, wherein the artery recanalization is endovascular thrombectomy are recited by claims 20, 21 and 28 of Appl. No. 19/650493.
The limitation of instant claim 34, where the single-stranded nucleic acid is administered intravenously by infusion is recited by claim 22 of Appl. No. 19/650493.
The limitations of instant claims 35 and 43, where the infusion has a duration of about 5 minutes, about 10 minutes, about 15 minutes, about 20 minutes, about 25 minutes, or about 30 minutes are recited by claim 23 of Appl. No. 19/650493.
The limitations of instant claims 37 and 49, where the single-stranded nucleic acid is administered at a dose of about 0.2 mg/kg, about 0.3 mg/kg, or about 0.4 mg/kg are recited by claim 24 of Appl. No. 19/650493.
The limitation of instant claim 39, where the single-stranded nucleic acid is formulated in phosphate buffered saline (PBS), pH 7.4, comprising magnesium chloride, and optionally A- trehalose dihydrate is recited by claim 25 of Appl. No. 19/650493.
The limitation of instant claims 41 and 42, where the administration of the single-stranded nucleic acid results in a decrease in infarct volume and results in a decrease in proinflammatory cytokines selected from the group consisting of interleukin-6 (IL-6), interferon-y (IFN-y), tumor necrosis factor alpha (TNF-a), interleukin-12p70 (IL-12p70), and any combination thereof is recited by claim 26 of Appl. No. 19/650493.
Instant claim 40 contains a wherein clause that recites the intended result 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.” Since the claims of Appl. No. 19/650493 recited the claimed method, the claims 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.
Response to Arguments
Applicant's arguments filed May 27, 2026 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 Lizasoain Hernandez, Struys and Zhang do not teach a method of improving the therapeutic outcome of a subject following an acute ischemic stroke that comprises a step of administering a single-stranded nucleic acid comprising the sequence of SEQ ID NO: 1 within 12 hours of symptom onset of the ischemic stroke or at a dose of at least about 0.2 mg/kg (Remarks pg. 10 para. 2). The Applicant’s amendments limiting claims 23 and 43 to include these new limitations necessitated the withdrawal of previous rejections. Applicant’s arguments are drawn to Lizasoain Hernandez, Struys and Zhang failing to teach this new limitation. However, this new limitation is addressed in the new rejection. Applicant is reminded that Struys is an evidentiary reference supporting the duration of infusion taught by Lizasoain Hernandez is a result effective variable that would be a matter of routine optimization. Struys is not a reference supporting a rejection under U.S.C. §103, and thus is not being used to establish obviousness of a particular limitation.
Applicant argues that the disclosure of instant application shows unexpected results. Specifically, Applicant states that there a decrease in infarct volume with a therapeutic window of up to 12 hours when a single-stranded nucleic acid comprising the sequence of SEQ ID NO: 1 is administered to rats (Remarks pg. 10 para. 4-5). As stated previously in the office action mailed on Feb. 27. 2. 2026, 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 that is greater than 0.2 mg/kg 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.
In addition, in further support of the claimed invention having unexpected results, Applicant argues that the instant application and Hernandez-Jimenez describe a Phase IIa Clinical Study of ApTOLL (a single-stranded nucleic acid comprising the sequence of SEQ ID NO: 1) for the treatment of acute ischemic stroke where human subjects were administered ApTOLL within 12 hours of the onset of symptoms. It was found that at a dose of 0.2 mg/kg the ApTOLL was safe and reduced mortality and disability at 90 days compared to placebo (Remarks pg. 10-11 bridging para.). Additionally, Applicant argues that in a further study by Ribo, ApTOLL was associated with improved health-related quality of life outcomes in patients with acute ischemic stroke and these results were unexpected (Remarks pg. 11 para. 1). However, these arguments were not found to be persuasive, since Lizasoain Hernandez teaches a method of using the claimed aptamer in treating acute ischemic perfusion and the method improves the therapeutic outcome of treating stroke (0029). As stated in the rejection, 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, it is expected that there would be improvement in symptoms of acute ischemic stroke. Therefore, the results presented in Hernandez-Jimenez and Ribo do appear to be unexpected.
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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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/EMILY A CORDAS/Primary Examiner, Art Unit 1632
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