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 .
Status
Claims 1, 8, 11, and 17-19 are pending. Claims 2-7, 9, 10, and 12-16 are canceled. Accordingly, Claims 1, 8, 11, and 17-19 are presented for examination.
Election/Restrictions
Applicant elected Group I (method of treating), AZ13711265 or IPA-3 as the small molecule in combination with IL-1β antibody and psoriasis as the disorder in the reply filed on 11/21/2024. The restriction requirement is made final.
NOTE: It was determined that AZ13711265 and IPA-3 are not distinct inventions but obvious variants of each other. However, the 4/1/2025 restriction requirement between group of both (AZ13711265 and IPA-3) and the remaining species of small molecules remains in place. Thus, the consideration and search has been restricted to the elected species.
Priority
This application is a 371 of PCT/EP2020/060701filed on 04/16/2020, which claims priority to EP19305502.7 filed on 04/17/2019.
Information Disclosure Statement
No Information Disclosure Statement was filed with Applicant’s recent response.
Withdrawn Rejections
Claims 1, 3, 8, 11, and 17-19 were rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification did not enable the claims as previously presented. Applicant’s amendment and corresponding reply pertaining to the newly added limitation have overcome the scope of enablement rejection made of record in the previous Office Action, specifically, the change to Claims 1 and 17 that removes language that encompasses embodiments of prevention.
Claim Rejections - 35 USC § 103
Rejection modified
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 1, 3, and 17 are rejected under 35 U.S.C. 103 as being unpatentable over
Goldminz et al. (“NF-κB: An essential transcription factor in psoriasis.” Journal of Dermatological Science; Volume 69, Issue 2, February 2013, Pages 89-94) in view of
Wong et al. (“IPA-3 inhibits the growth of liver cancer cells by suppressing PAK1 and NF-κB activation.” PLoS One. 2013 Jul 19;8(7):e68843. doi: 10.1371/journal.pone.0068843. PMID: 23894351; PMCID: PMC3716906), and
McCoull et al. (“Optimization of Highly Kinase Selective Bis-anilino Pyrimidine PAK1 Inhibitors.” ACS Med. Chem. Lett. 2016, 7, 1118−1123. DOI: 10.1021/acsmedchemlett.6b00322).
Claimed invention
A method of reducing severity of psoriasis in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of AZ13711265, and
wherein the therapeutically effective amount of the AZ13711265 reduces severity of at least one symptom of psoriasis selected from the group consisting of erythema, scaling, and total psoriasis area and severity index (PASI) score.
Prior art
Goldminz teaches that NF-κB is an essential nuclear transcription factor in immune cell and keratinocyte biology, and the pathogenesis of psoriasis. See p. ‘Conclusion’ section at pp. 93-94. Several studies have demonstrated baseline elevations of NF-κB activity in lesional and non-lesional psoriatic skin with reductions in NF-κB levels following systemic and localized treatments. See p. 91, last para. Several anti-psoriatic therapies, including tumor necrosis factor-α blockers and glucocorticoids, reduce active NF-κB levels and related down-stream elements. See abstract. The classic clinical and histological features of psoriasis arise with scaly, erythematous, indurated plaques demonstrating hyperkeratosis, parakeratosis, acanthosis, elongated rete ridges and a mixed inflammatory infiltrate. See p. 90 section 2.1.
While Goldminz teaches that NF-κB is essential in the pathogenesis of psoriasis and several anti-psoriatic therapies reduce active NF-κB levels, Goldminz does not expressly teach AZ13711265 (PAK1 inhibitor).
However, it was known that PAK1 inhibition can be used to reduce NF-κB activity in order to treat a disease that is associated with increased NF-κB activity. For example, Wong investigated the PAK1 inhibitor, IPA-3, for its potential to suppress hepatocarcinogenesis (HCC) through a series of in vitro and in vivo experiments. See abstract; see also p. 10, 1st para. under ‘Discussion’. It had been proposed that of NF-κB transcription factors are associated with malignancy by imparting an anti-apoptotic effect to the cancer cells. See p. 11, last para. Wong demonstrated that IPA-3 suppressed HCC and the mechanisms through which it suppresses HCC cell growth are by blocking activation of NF-κB and by enhancement of apoptosis. See abstract; see also p. 11, last para.
McCoull teaches two PAK-1 inhibitors, AZ13705339 and AZ13711265. AZ13711265 displayed better pharmacokinetic properties and was proposed for in vivo use. See McCoull, abstract; para. bridging pp. 1119-1120; see also p. 1121, last para. to p. 1122, last para.
A person of ordinary skill in the art (POSA) would have found it obvious to reduce severity of symptoms of psoriasis by administering an effective amount of AZ13711265 or IPA-3 to reduce disease symptoms/indications in a subject because:
Goldminz teaches that NF-κB is essential in the pathogenesis of psoriasis and anti-psoriatic agents reduce active NF-κB levels,
Wong, using IPA-3 as a PAK1 inhibitor, demonstrates that PAK1 inhibition reduces NF-κB activity and this mechanistic connection can be used to treat a disease that is associated with increased NF-κB activity, and
McCoull teaches that AZ13711265 is a PAK1 inhibitor proposed for in vivo use due to its pharmacokinetic properties.
The ordinary skilled artisan would have reasonably understood that AZ13711265 or IPA-3 would provide PAK1 inhibition that reduces NF-κB activity, and this reduction in activity would be beneficial in treatment of a disease associated with increased NF-κB activity such as psoriasis. A reduction in erythema or scaling corresponds to a reduction in the underlying inflammatory reasons associated with psoriatic lesions as indicated by Goldminz. Because psoriasis is defined by inflamed, erythematous and scaly plaques, the POSA would reasonably seek to apply an effective amount of the inhibitor such that these indications of the disease are reduced. Thus, Claims 1 and Claim 17 are rendered prima facie obvious by the prior art.
Claim 3 limits the inhibitor to a small molecule. As mentioned above, McCoull teaches AZ13711265, which is a small molecule.
Response to arguments
Applicant's arguments have been fully considered but have not been found to be persuasive.
Applicant argues that IPA-3 disclosed by Wong is an allosteric PAK1 inhibitor, whereas AZ13711265 is an ATP-competitive PAK1 inhibitor, and that Wong’s disclosure of IPA-3 selectivity and potential off-target effects of ATP-binding pocket inhibitors would have taught away from the claimed use of AZ13711265. However, the rejection does not rely on IPA-3 and AZ13711265 being interchangeable inhibitors or on Wong teaching AZ13711265 itself. Together, the references provide the rationale to practice the claimed method: Goldminz teaches that NF-kB is involved in the pathogenesis of psoriasis and that anti-psoriatic treatment reduces active NF-kB levels. Wong demonstrates using the PAK1 inhibitor IPA-3, that inhibition of PAK1 reduces NF-kB activity, thereby establishing a mechanistic connection between PAK1 inhibition and the reduction of NF-kB activity. McCoull further teaches AZ13711265 as a PAK1 inhibitor proposed for in vivo use based on its pharmacokinetics properties. Accordingly, a POSA would have had reason to administer an effective amount of AZ13711265 to a subject with psoriasis because the prior art teaches 1) that reducing NF-kB activity is beneficial in psoriasis, 2) that PAK1 inhibition reduces NF-kB activity, and 3) that AZ13711265 is a PAK1 inhibitor suitable for in vivo use. Wong’s preference for IPA-3 or discussion of potential off-target effects of ATP-competitive inhibitors does not negate these teachings or establish that AZ13711265 would have been unsuitable for therapeutic use, particularly in view of McCoull’s teaching of AZ13711265 for in vivo use.
Applicant further argues that Wong lacks biological data demonstrating treatment of psoriasis with IPA-3 and that the references do not expressly disclose treating psoriasis with AZ13711265. Obviousness does not require the prior art to have actually performed the claimed treatment where the combined teachings provide a reason to pursue it with a reasonable expectation of success. Here, the cited teachings would have suggested using PAK1 inhibition, including AZ13711265, to reduce psoriasis-associated symptoms such as erythema and scaling.
Therefore, the rejection is deemed to still be proper and is, therefore, maintained.
B. Claims 8 and 18 are rejected under 35 U.S.C. 103 as being unpatentable over Goldminz et al. (cited above) in view of Wong et al. (cited above) and McCoull et al. (cited above), as applied to Claims 1, 3 and 17 above, taken further in view of Skendros et al. (“Successful response in a case of severe pustular psoriasis after interleukin-1β inhibition.”) Br J Dermatol. 2017 Jan;176(1):212-215. doi: 10.1111/bjd.14685. Epub 2016 Oct 12. PMID: 27105586.)
Claimed invention
Claims 8 and 18 limit claim 1 and claim 17, respectively, further comprising administering to the subject a neutralizing monoclonal anti-IL-1β antibody in combination with the PAK-1 inhibitor.
Prior art
The disclosures for Goldminz, Wong and McCoull and how they meet the limitations of Claim 1 are outlined above. Their combination does not expressly teach a neutralizing monoclonal anti-IL-1β antibody in combination with the PAK-1 inhibitor, AZ13711265.
However, canakinumab is a monoclonal anti-interleukin-1β (IL-1β) antibody that has demonstrated efficacy in the treatment of psoriasis. See Skendros, title; summary.
A person of ordinary skill in the art (POSA) would have found it obvious to combine canakinumab with AZ13711265 for the treatment of psoriasis because Goldminz, Wong and McCoull suggest treating psoriasis with AZ13711265 while Skendros teaches that canakinumab effectively treats psoriasis. The artisan would have used them together seeking to combine the anti-psoriasis efficacy of canakinumab with the beneficial anti-psoriatic treatment suggested for AZ13711265 by Goldminz, Wong and McCoull.
Response to arguments
Applicant relies on arguments addressed above. Therefore, the rejection is deemed to still be proper and is, therefore, maintained.
C. Claims 11 and 19 are rejected under 35 U.S.C. 103 as being unpatentable over Goldminz et al. cited above) in view of Wong et al. (cited above) and McCoull et al. (cited above), as applied to Claims 1, 3 and 17 above, taken further in view of C.R. DeLiccia (US 4,131,652).
Claimed invention
Claims 11 and 19 limit claims 1 and 17, respectively, wherein the PAK-1 inhibitor is formulated as a cream for a topical administration.
Prior art
The disclosures for Goldminz, Wong and McCoull and how they meet the limitations of Claim 1 are outlined above. Their combination does not expressly teach a cream formulation for topical administration.
However, DeLiccia teaches that anti-psoriatic treatment can be formulated as a cream. See title; col. 1, lines 40-47.
A person of ordinary skill in the art (POSA) would have found it obvious to incorporate the PAK1 inhibitor, AZ13711265, into a cream as a vehicle to deliver the agent to the skin in order to treat psoriasis because DeLiccia teaches cream is a suitable vehicle for delivering an anti-psoriatic agent. The artisan would have reasonably presumed that a cream formulation containing AZ13711265 would be suitable to provide the agent to the skin to treat psoriasis.
Response to arguments
Applicant relies on arguments addressed above. Therefore, the rejection is deemed to still be proper and is, therefore, maintained.
Conclusion
No claims are 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CHRIS E SIMMONS whose telephone number is (571)272-9065. The examiner can normally be reached M-F: 9:30-6:00p.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, James H. Alstrum-Acevedo can be reached on (571) 272-5548. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/CHRIS E SIMMONS/Examiner, Art Unit 1622
/JAMES H ALSTRUM-ACEVEDO/Supervisory Patent Examiner, Art Unit 1622
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