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 .
Response to Amendment
2. Applicant’s Response, submitted August 19, 2025, has been reviewed by the examiner.
3. No claim is amended, canceled, or added.
Status of the Claims
4. Claims 41-59 are present in the application.
5. Applicant previously elected Group I and the species of (1) the compound of Formula (II) of claim 45 (readable on claims 41-59); (2) haemorrhagic stroke (readable on claims 41-46, 49-52 and 55-59); (3) subarachnoid haemorrhage (readable on claims 41-46, 49, 51, and 55-59); and (4) thrombectomy (readable on claims 41-55 and 59).
6. The non-elected species remain withdrawn from consideration pursuant to 37 CFR 1.142(b) as directed to non-elected subject matter without traverse, i.e., claims 47, 48, 50, 52-54, and 56-58 are herein withdrawn.
7. Claims 41-46, 49, 51, 55 and 59 are under examination with the elected species and are the subject of this office action.
Information Disclosure Statement
8. The information disclosure statement (IDS) submitted on July 16, 2025, is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement has been considered by the examiner, please refer to the initialed and signed PTO-1449 form, attached herewith.
Previous Claim Rejections - 35 USC § 103
9. The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
10. Claims 41-46, 49, 51 and 59 remain rejected under 35 U.S.C. 103 as being unpatentable over Edvinsson and Ansar, WO 2008/121044 (published October 9, 2008), as evidenced by Moawad, Heidi, Verywellhealth.com (published October 19, 2023), and further in view of Cheng and Tian, Molecules (published September 26, 2017).
Claim 41 is drawn to a method of treating or reducing the risk of developing a stroke in a subject in need thereof, (more specifically, a haemorrhagic stroke resulting from subarachnoid haemorrhage (SAH) (claim 51, and embraced by claims 46 and 49)), comprising administering a compound of formula (I), more specifically the compound of formula (II):
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, i.e., trametinib, (claim 45, and embraced by claims 42-44)) to the subject in need thereof, thereby treating or reducing the risk of developing a stroke, and
wherein the compound is administered to the subject up to 6 hours subsequent to the onset of stroke, or wherein the compound is administered one or more times daily for up to 3 days subsequent to the onset of the stroke (claim 59).
11. Edvinsson teaches a rat model of subarachnoid hemorrhage (SAH), comprising administering U0126, a known MEK1/MEK2 inhibitor, to treat middle cerebral artery occlusion (MCAO) resulting from SAH in said rat, in a dosage amount of 30 mg/kg (Page 10, lines 5-15). And, as evidenced by Moawad, “an MCA [(middle cerebral artery)] stroke can also be caused by a ruptured artery. This is known as a hemorrhagic stroke.” (Page 1, second paragraph). Edvinsson teaches that a dose of 30 mg/kg was the lowest dose that elicited a clear significant effect on infarct (aka stroke) volume in said rat; therefore, Edvinsson teaches the limitation of treating hemorrhagic stroke. Edvinsson teaches that the rat was injected intraperitoneally with U0126 at 6 h, 12 h, or at 24 h following the MCAO (page 10, lines 9-10), which meets the limitation of “up to 6 hours subsequent to the onset of stroke” and the limitation of “one or more times daily for up to 3 day subsequent to the onset of the stroke,” required by claim 59.
12. Thus, one of skill in the art before the effective filing date of the claimed invention would have reasonably considered treating a hemorrhagic stroke (resulting from a subarachnoid hemorrhage) in a subject in need thereof, comprising administering the MEK1/2 inhibitor U0126 to said subject.
13. Edvinsson does not teach the administration of Applicant’s instant compound of claim 45 (aka Trametinib).
14. Yet, Cheng summarizes the activity of selective MEK inhibitors including U0126 and Trametinib, wherein U0126 demonstrates inhibitory activity on MEK1 (IC50 of 70 nM) and MEK2 (IC50 of 60 nM), (see Table 3 at page 12, and page 13, paragraph under “5.7 U0126”). Trametinib, the first MEK inhibitor approved by FDA, demonstrates higher potency against MEK1/2 kinases: IC50 of 0.7 nM against MEK1 and IC50 of 0.9 nM against MEK2 (see Table 1 at pages 2-3, and page 3, under “3.1 Trametinib”). Thus one of skill in the art before the effective filing date of the claimed invention would have been motivated to modify Edvinsson by substituting the instantly recited MEK inhibitor trametinib for U0126 in the treatment of hemorrhagic stroke in a subject in need thereof, with a reasonable expectation of success. And, as noted by the court in In re Font, 675 F.2d 297 (CCPA 1982), an express suggestion to substitute one equivalent component (i.e., an equivalent MEK inhibitor) for another is not necessary to render such substitution obvious. In the instant case, (1) the prior art element of Edvinsson performs the function specified in the claim with only insubstantial differences; (2) the claimed component (i.e., the MEK inhibitor trametinib) and its function was known in the art; (3) a person of ordinary skill in the art would have recognized the interchangeability of the elements and could have substituted one known element for another; and (4) the results of the substitution would have been predictable, i.e., successful treatment or reduction of risk of developing a stroke resulting from a subarachnoid hemorrhage in a subject in need thereof.
As such, claims 41-46, 49, and 51 are prima facie obvious.
15. Claim 55 is rejected under 35 U.S.C. 103 as being unpatentable over Edvinsson and Ansar, WO 2008/121044, as evidenced by Moawad, Heidi, Verywellhealth.com (2023), in view of Cheng and Tian, Molecules (2017), as applied to claims 41-46, 49, and 51, above, and further in view of Consoli et al., Stroke (2018).
Claim 41 is addressed in detail, above.
CLAIM 55 is drawn to claim 41, wherein trametinib is administered prior to, concurrent with, or subsequent to thrombectomy.
16. Edvinsson as evidenced by Moawad in view of Cheng teach the treatment of a hemorrhagic stroke, (resulting from a subarachnoid hemorrhage), in a subject in need thereof, comprising administering the MEK1/2 inhibitor trametinib to said subject, but do not teach the limitation of a thrombectomy procedure in the subject.
17. Yet, Consoli et al. suggest endovascular treatment strategies and devices, in particular a thrombectomy, for treating middle cerebral artery occlusion in a patient in need thereof (see page 1286, under “Background and Purpose”). Consoli et al. teach that thrombectomy resulted in successful recanalization at the occlusion site in 100% of the patients (see page 1286, under “Results”).
18. As such, one of skill in the art before the effective filing date of the claimed invention would have been motivated to employ a thrombectomy procedure as an additional treatment strategy prior to, concurrent with, or subsequent to administration of trametinib in a subject having suffered a stroke in the form of a middle cerebral artery occlusion. It would have been obvious to one skilled in the art before the effective filing date of the claimed invention to employ a thrombectomy procedure as an additional treatment strategy with administration of trametinib in a subject having suffered a stroke in the form of a middle cerebral artery occlusion, with a reasonable expectation of success. And, a subject that has suffered a stroke meets the limitation of a subject in need thereof.
As such, claim 55 is prima facie obvious.
Response to Arguments
19. Applicant traverses the obviousness rejection of claims 41-46, 49, 51 and 59 over Edvinsson as evidenced by Moawad, in view of Cheng and Tian, and argues the following points:
(i) Applicant contends that the rejection presumes that Edvinsson would have taught a person of ordinary skill in the art that every and any molecule that exhibits some MEK1/2 inhibition would be effective in a MCAO rat model. Applicant argues that Edvinsson does not describe any mechanistic studies that would suggest that U0126's activity in the MCAO rat model is a direct result of U0126's MEK inhibition. Applicant argues that Edvinsson only tested U0126 and those findings were not replicated with any other MEK inhibitors, and that at best, Edvinsson suggests that U0126 may be useful in the MCAO rat model, but not that all MEK1/2 inhibitors are similarly useful. Applicant alleges that the rat model described in Edvinsson is not representative of the disorders treated according to the claimed invention. Applicant argues that the claims are non- obvious at least because Applicant has shown that trametinib is superior to U0126, which would not have been expected by one skilled in the art.
Applicant contends that Edvinsson does not disclose Applicant's claimed compound of formula (I) for any uses, including trametinib (structure shown below), and that Applicant's claimed compounds share no structural similarities with Edvinsson's inhibitors such that one skilled in the art would have no reason to use Applicant's structurally unrelated compounds for any reason that Edvinsson might suggest.
20. Applicant's arguments have been fully considered but they are not persuasive. In response to Applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). In this case, the primary reference, Edvinsson, suggests the administration of MEK1/2 inhibitors as a class of inhibitors for treating stroke, i.e.,
“[t]he invention relates to the use of at least one inhibitors selected from the group consisting of protein kinase C (PKC), raf, MEK1/2, or ERK1/2, for the manufacturing of a medicament to be administrated from >1 up to 12 from diagnosis of an ischemic disease…. The inhibitor may be different but the same results have been found using different inhibitors (see examples)…. Other potential inhibitors are U0126 which is a potent inhibitor of MEKl and MEK2.”
(Page 5, first paragraph under “Medicament”). Regarding Applicant’s allegations that Edvinsson does not describe any mechanistic studies suggesting that U0126's activity in the MCAO rat model is a direct result of U0126's MEK inhibition, and that Edvinsson only tested U0126 and the findings were not replicated with any other MEK inhibitors, conclusive proof of efficacy is not required to show a reasonable expectation of success. Acorda Therapeutics, Inc. v. Roxane Lab., Inc., 903 F.3d 1310, 1333, 128 USPQ2d 1001, 1018 (Fed. Cir. 2018) ("This court has long rejected a requirement of ‘[c]onclusive proof of efficacy’ for obviousness." (citing to Hoffmann-La Roche Inc. v. Apotex Inc., 748 F.3d 1326, 1331 (Fed. Cir. 2014); PharmaStem Therapeutics, Inc. v. ViaCell, Inc., 491 F.3d 1342, 1364 (Fed. Cir. 2007); Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348, 1364, 1367–68 (Fed. Cir. 2007) (reasoning that "the expectation of success need only be reasonable, not absolute")). Edvinsson discloses the administration of U0126 in the SAH model of
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Example 2, but also suggests employing different inhibitors to obtain the same result, including those that inhibit the MEK1/2 pathway (see quoted section above). And, Cheng compares the activity of selective MEK inhibitors including U0126 and Trametinib, wherein Trametinib demonstrates higher potency against MEK1/2 kinases than U0126. As such, one skilled in the art before the effective filing date of the claimed invention would have reasonably considered substituting the MEK1/2 kinase inhibitor Trametinib for U0126 in the MCAO rat model of SAH.
(ii) Applicant argues that the Examiner alleged that Moawad teaches that "a middle cerebral artery occlusion (MCAO) is a stroke that can be caused by a ruptured artery, i.e., a hemorrhagic stroke." (Action at 4); however, that is not what Moawad teaches: “Moawad is a general health article on the causes, symptoms and treatment options for middle cerebral artery stroke. Moawad notes that a middle cerebral artery (MCA) stroke can be caused by a ruptured artery, i.e., a hemorrhagic stroke." (Applicant’s Remarks, page 7). Applicant alleges that Moawad does not teach MCAO may be a hemorrhagic stroke because
MCAO is a "middle cerebral artery occlusion," with occlusion in this context generally meaning blockage of an artery or blood vessel. Thus, since Edvinsson is directed to treating hemorrhagic stroke, there would be no motivation to combine the teachings of Edvinsson with Moawad.
21. Applicant's arguments have been fully considered but they are not persuasive. In response to Applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. In this case, the evidentiary reference Moawad, discloses that “an MCA [(middle cerebral artery)] stroke can also be caused by a ruptured artery. This is known as a hemorrhagic stroke.” (Page 1, second paragraph). The primary reference, Edvinsson, suggests the administration of MEK1/2 inhibitors for treating stroke in a rodent model of MCAO, which is the stroke model commonly used in pre-clinical stroke studies in rats and mice to replicate the effects of middle cerebral artery (MCA) stroke in humans. As both Edvinsson and Moawad are directed to treating MCA stroke, (wherein Edvinsson employs an MCAO model), one of skill in the art seeking an improved method of treating haemorrhagic stroke in the MCA before the effective filing date of the claimed invention would have been motivated to combine the references.
(iii) Applicant argues that a skilled person would not be motivated to substitute Edvinsson's U0126 for Cheng and Tian's trametinib to treat a hemorrhagic stroke resulting from SAH. Applicant alleges that Cheng and Tian is only a review of MEK inhibitors and their use in cancer treatments, including trametinib and U0126, and does not discuss using trametinib for treating hemorrhagic stroke, such that the skilled person in the art would not turn to the teachings of Cheng and Tian in seeking to find alternative treatments for stroke.
Applicant argues that even if one were to use Cheng and Tian's trametinib (and U0126) in Applicant's claimed methods, there would be no expectation that there would be such a difference in activity between the two compounds. Applicant alleges that as shown in the instant examples, trametinib was superior to U0126, and other MEK inhibitors, in the Specification at page 30, line 30 through page 31, line 5:
“It is known that cerebral arteries treated with 10 pM U0126 in 48 hours OC shows an inhibitory effect on the ETs specific S6c-induced contractility. In the present disclosure, 1 mM U0126 showed no significant effect, whereas trametinib and PD0325901 at 1 mM almost completely inhibited the contractile response after 48 hours organ culture (Fig. 1A). Id. at page 32, lines 5-8.
Applicant argues that Trametinib was found to have high potency, indicating that it can be applied at lower doses than the current drug of choice, U0126. Applicant contends that the first drug of choice U0126 was found to have similar advantageous effects in vivo intrathecally, but due to its poor solubility it was not possible to transform this agent to systemic administration. Trametinib was found to have excellent solubility and potency which demonstrates that it can be used in lower volumes, allowing for systemic use while still showing advantageous anti-SAH parameters. Id. at page 35, lines 5-11.
22. Applicant's arguments have been fully considered but they are not persuasive. In response to Applicant's argument regarding the teaching of Cheng, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. In this case, Cheng compares the activity of selective MEK inhibitors including U0126 and Trametinib, wherein Trametinib demonstrates higher potency against MEK1/2 kinases than U0126. As such, one skilled in the art before the effective filing date of the claimed invention would have reasonably considered substituting the MEK1/2 kinase inhibitor Trametinib for U0126 in the MCAO rat model of SAH disclosed by Edvinsson.
In response to Applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which Applicant relies (i.e., the unexpectedly beneficial effects of trametinib or PD0325901 for treating haemorrhagic stroke caused by subarachnoid haemorrhage when administered at a low dose of 1 mM) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). In other words, the "objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support." See MPEP 716.02(d). It is recommended that the instant claims be limited to the treatment of haemorrhagic stroke caused by subarachnoid haemorrhage comprising administering trametinib at a dose of 1 mM, which is commensurate in scope with the results demonstrated in Example 11, for example (at pages 55-57 of the instant Specification).
Conclusion
23. Claims 41-59 are present in the application. Claims 47, 48, 50, 52-54, and 56-58 are presently withdrawn from consideration as drawn to non-elected subject matter. Claims 41-46, 49, 41, 55, and 59 remain rejected. No claim is presently allowed.
24. 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.
25. Any inquiry concerning this communication or earlier communications from the examiner should be directed to JANET L COPPINS whose telephone number is (571)272-0680. The examiner can normally be reached Monday-Friday 8:30AM-5PM EST.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Amy L Clark can be reached at 571-272-1310. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/JANET L COPPINS/Examiner, Art Unit 1628
/AMY L CLARK/Supervisory Patent Examiner, Art Unit 1628