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, 3, 8, 11, and 17-19 are pending, with Claims 17-19 newly added. Previously withdrawn Claims 2, 9, 10, and 12-14 have been cancelled by Applicant’s recent amendment. As a result, Claims 2, 4-7, 9, 10, and 12-16 are canceled. Accordingly, Claims 1, 3, 8, 11, and 17-19 are presented for examination.
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 3/4/2026 has been entered.
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.
Response to arguments
Applicant arguments are non-persuasive because the restriction was made final.
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Withdrawn Rejections
Claim 3 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends. Applicant’s amendment and corresponding reply pertaining to the newly added limitation have overcome the 35 USC 112(d) rejection made of record in the previous Office Action, specifically, the narrowing of claim 3 to require the specific inhibitor, AZ13711265.
Claim Objections
New objection, necessitated by amendment
Claim 1 is objected to because of the following informalities:
Claim 1,
Lines 8-9: the term “6-[2-Chloro-4-(5-thiazolyl)phenyl]- 8-ethyl-2-[[4-(4-methyl-1-piperazinyl) phenyl] amino] pyrido[2,3-d]pyrimidin-7-(8H)-one” contains improper internal spacing that should be removed. For example, there is an extraneous space in “phenyl]- 8-ethyl,” and additional extraneous spaces in “piperazinyl) phenyl] amino] pyrido”.
Line 10: a comma should be added before the term "or".
Line 13: a comma should be added after the term "scaling".
Appropriate correction is required.
Claim Rejections - 35 USC § 112 – Scope of Enablement
New rejection
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1, 3, 8, 11, and 17-19 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for reducing the severity of psoriasis, does not reasonably provide enablement for “treating” psoriasis (as expanded be definition) or for any broad curative, preventative, or prophylactic intervention of psoriasis. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
The test of enablement requires a determination of whether the disclosure, when filed, contained sufficient information regarding the subject matter of the claims as to enable one skilled in the pertinent art to make and use the claimed invention. That standard is still the one to be applied. In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988). Accordingly, even though the statute does not use the term “undue experimentation,” it has been interpreted to require that the claimed invention be enabled so that any person skilled in the art can make and use the invention without undue experimentation. In re Wands, 858 F.2d at 737, 8 USPQ2d at 1404 (Fed. Cir. 1988). Keeping that in mind, the Wands factors are relevant to the instant fact situation for the following reasons:
The nature of the invention:
The invention relates to a method for the treatment of NLRP3 inflammasome mediated IL-1beta dependent disorders with a PAK-1 inhibitor. Treatment is defined broadly to include not only therapeutic intervention, but also prophylaxis and prevention. See Applicant’s definition on page 3, lines 5-9 of the specification filed on October 15, 2021. The invention is based on the recognition that activation of the NLRP3 inflammasome and subsequent IL-1beta maturation is dependent on signaling through p21-activated kinases (PAK1/PAK2). Inhibition of PAK1 and/or PAK2 disrupts this signaling cascade, thereby reducing caspase-1 activation and IL-1beta production to treat NLRP3 inflammasome-mediated disorders.
Breadth of claim:
Claim 1 broadly recites:
“a method of treating a psoriasis in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a PAK-1 inhibitor…”
Claim 17 recites:
“a method of treating a subject suffering from psoriasis, comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of AZ13711265…”
However, the claim scope (as expanded by definition) exceeds what the specification enables because it defines “treating” to include prophylactic or preventative measures and even encompasses treating subjects at risk of developing psoriasis:
“As used herein, the terms ‘treating’ or ‘treatment’ refer to both prophylactic or preventive treatment as well as curative or disease modifying treatment, including treatment of subject at risk of contracting the disease or suspected to have contracted the disease as well as subject who are ill or have been diagnosed as suffering from a disease or medical condition, and includes suppression of clinical relapse. The treatment may be administered to a subject having a medical disorder or who ultimately may acquire the disorder, in order to prevent, cure, delay the onset of, reduce the severity of, or ameliorate one or more symptoms of a disorder or recurring disorder, or in order to prolong the survival of a subject beyond that expected in the absence of such treatment.”
See Specification p. 3. Emphasis added.
Yet, the specification does not provide guidance or working examples demonstrating how such prevention can be achieved. Moreover, the state of the art indicates that psoriasis is a chronic, relapsing condition for which prevention of disease onset is not established, but rather management of symptoms and flare-ups is the standard approach.
Thus, the breadth of the claims are broader than the enabling support provided by the specification. While Claim 17 is better positioned, it still encompasses embodiments of curing.
State and predictability of the art:
Psoriasis is a chronic, immune-mediated disorder involving complex interactions among multiple cell types, including keratinocytes, dendritic cells and T cells, and that therapy is directed to management of symptoms rather than prevention or cure (see Zhu et al. “Treatments in psoriasis: from standard pharmacotherapy to nanotechnology therapy”. Postepy Dermatol Alergol. 2022 Jun;39(3):460-471. doi: 10.5114/ada.2021.108445. Epub 2021 Aug 16. PMID: 35950130; PMCID: PMC9326914 - particularly, ‘Pathophysiology’ section at p. 460). Zhu reports “modern medicine has not discovered the complete cure for psoriasis” and that treatments “suppress the condition and ease symptoms but do not completely cure psoriasis.” Modern state of the art indicates management of symptoms and flare-ups of psoriasis is the standard approach (see Zhu et al., ‘Conclusions’ section at p. 467.)
Consistent with these teachings, a systematic review of interventions for psoriasis reports that available treatments and lifestyle interventions are directed toward reducing disease severity and improving quality of life, with outcomes described as “may reduce the severity of psoriasis” and “probably improves quality of life”, indicating variable and limited effects rather than prevention or cure (see Ko et al. “Lifestyle changes for treating psoriasis.” Cochrane Database Syst Rev. 2019 Jul 16;7(7):CD011972. doi: 10.1002/14651858.CD011972.pub2. PMID: 31309536; PMCID: PMC6629583 – particularly, abstract; ‘Author’s conclusion’ at p. 2; ‘Key results’ at p. 3). These teachings further demonstrate that even broad intervention strategies do not provide predictable or reliable methods for preventing the onset of psoriasis.
Therefore, state of the art recognizes that psoriasis prevention or prophylaxis is not predictable.
Relative skill level:
One of ordinary skill in the art is one with access to reagents, tools and equipment used for diagnosing disease, performing tests and/or administering treatment to individuals. The skilled artisan also has many years of training and experience in either the clinical or laboratory environment or both. Therefore, it is clear that the level of skill of one in the art is high. However, this high level of skill is overcome in view of the limited teachings provided by the specification and the unpredictable state of the art, it would require the skilled artisan undue experimentation to make and use the invention commensurate to the scope of the claims.
The amount of direction or guidance provided and the presence or absence of working examples:
The amount of guidance and working examples provided in the specification is limited and does not enable the full scope of the claimed invention. The disclosure describes mechanistic studies showing that PAK1/PAK2 signaling is involved in activation of the NLRP3 inflammasome and IL-1beta maturation. These include in vitro and in vivo experiments. In vitro assays include macrophages treated with LPS and CNF1 as well as Caspase-1 activation measured using FAM- FLICA, PAK effector pull down assay (see Fig. 1-2). In vivo support for psoriasis, however, is limited to a single imiquimod-induced psoriasis-like model where administration of a PAK inhibitor reduced erythema and scaling scored using the PASI score (see Fig. 5). These results are limited to modulating pathway and symptom reduction in a specific model, but do not provide guidance for achieving prophylactic treatment, prevention of disease onset, or cure of psoriasis.
The quantity of experimentation necessary:
In view of the breath of the claim, which encompasses prophylactic and curative treatment, the lack of guidance in the specification for achieving such embodiments, and the unpredictable nature if psoriasis and its treatment as reflected in the state of the art, a person of ordinary skill in the art (POSA) would not have been able to practice the full scope of the claimed invention without undue experimentation. Accordingly, the claim is not enabled under 35 U.S.C. § 112(a).
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 treating psoriasis in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a PAK-1 inhibitor such AZ13711265, and
wherein the therapeutically effective amount of the PAK-1 inhibitor reduces 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 treat 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 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 the present invention demonstrates that inhibition of PAK-1 alone is sufficient to treat psoriasis, including reduction of erythema. However, the newly added limitation reciting erythema reduction does not patentably distinguish the claimed invention from the prior art. Psoriasis was well known in the art as an inflammatory skin disease characterized by erythematous (red), scaly plaques: “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 Goldminz). Thus, erythema is a fundamental and defining symptom of psoriasis. Because erythema is characteristic in psoriatic plaques, treatment that reduces psoriatic disease activity would reasonably be expected to reduce associated erythema as an intrinsic or expected result. Moreover, such reduction in this symptom of psoriasis would have been an obvious goal of the POSA to minimize pathognomonic findings by administering psoriasis treatment.
Applicant argues that the prior art does not teach the use of a selective PAK-1 inhibitor. However, AZ13711265 is a selective PAK-1 inhibitor and Wong teaches that NF-kB is inhibited by PAK-1 inhibition. Wong, therefore, provides a clear mechanistic link between specific inhibition of PAK-1 – with a PAK-1-inhibiting agent such as AZ13711265 (McCoull) – and suppression of an inflammatory pathway, i.e., NF-kB, which Goldminz teaches is central to psoriasis.
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.
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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