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
Non-Final Rejection
Claim Status
Claims 1-11, 13-18 and 21 were subjected to Restriction/Election Requirement.
Claims 1-11, 13-18 and 21 are pending examination.
Priority Status
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No foreign priority was claimed in the Instant Application; EFD is 04/29/2019.
Information Disclosure Statement
All references have been considered in the one (1) IDS(s) filed 04/02/2025 unless marked with a strikethrough.
Drawings
The one (1) drawing submission filed on 10/27/2021 has been accepted by the Examiner.
Response to Restriction/Election of Species
In Response to the Restriction and Species Election Requirement dated 07/14/2025:
Applicant elected Group I (claims 1-10) directed to an ophthalmic composition comprising a MAPK/ERK kinase.
The election was made without traverse.
Group II: Claims 11, 13-18, and 21, drawn to a method of treating ocular disease or condition is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected inventions.
Further, Applicant elected a species for each of the following variables:
Selumetinib as a species for MAPK/ERK kinase (MEK1/2) inhibitor;
Ulixertinib as a species of ERK inhibitor; and
Polyols as a species of a pharmaceutically acceptable ophthalmic excipient.
If the elected specie is not identified in the art, the Examiner will expand her search to additional species per MPEP 802.03.
The elected specie was identified in the art.
Rejection on the claims is seen below in the 102/103 rejection.
Claims 1-9 are directed to the elected species.
Claim Interpretation
The transitional term used in the limitation of “An ophthalmic composition comprising a MAPK/ERK kinase (MEK) inhibitor and phosphate buffered saline (PBS)” is considered open-ended according to:
MPEP 2111.03.I:
The transitional term “comprising”, which is synonymous with “including,” “containing,” or “characterized by,” is inclusive or open-ended and does not exclude additional, unrecited elements or method steps. See, e.g., Mars Inc. v. H.J. Heinz Co., 377 F.3d 1369, 1376, 71 USPQ2d 1837, 1843 (Fed. Cir. 2004) (“[L]ike the term ‘comprising,’ the terms ‘containing’ and ‘mixture’ are open-ended.”).
With respect to BVD-523 (Ulixertinib) a novel, reversible, ATP-competitive ERK1/2 inhibitor & AZD6244 (Selumetinib, ARRY-142886) a novel small molecule MEK1/2 inhibitor as noted in the Instant Case.
Ulixertinib is used in the art as treatment in a wide range of tumors (as evidenced in PubChem) and Selumetinib is known as a mitogen-activated protein kinase kinase (MEK) inhibitors in the Raf-MEK-ERK signalling pathway known to be implemented in several types of malignancies.
Thus the prior art structure is capable of performing the intended use as recited in the preamble meets the claim. See, e.g., In re Schreiber, 128 F.3d 1473, 1477, 44 USPQ2d 1429, 1431 (Fed. Cir. 1997).
Claim Objections
Claims 1 and 8 objected to for the following:
Claim 1 recites the limitation “An ophthalmic composition comprising a MAPK/ERK kinase (MEK) inhibitor and phosphate buffered saline (PBS).”
Claim 8 recites the limitation "The ophthalmic composition of claim 1, wherein the MAPK/ERK kinase (MEK) inhibitor is an ERK inhibitor.
The Applicant’s election of Selumetinib as a MAPK/ERK kinase, and Ulixertinib as an ERK inhibitor, are not properly distinguished in the claims.
Selumetinib and ulixertinib are both targeted therapies that inhibit the MEK/ERK pathway, but they work at different points in the pathway. A MEK inhibitor is not an ERK inhibitor; it targets the MEK protein, which is upstream of ERK in the MAPK pathway. While an ERK inhibitor directly blocks ERK itself. By inhibiting MEK, a MEK inhibitor indirectly reduces ERK activity, but an ERK inhibitor provides more direct and specific blocking of the final kinase in the cascade.
Examiner suggests a recitation indicating distinction between the two kinase inhibitors, such as “…MEK and/or ERK kinase inhibitor”. Although not rising to the level of a rejection, this issue should be resolved.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
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.
Claim 4 is 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 4 contains the trademark/trade name Carbopol.
Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name.
In the present case, the trademark/trade name is used to identify/describe Carbopol is the brand name for a specific line of acrylic acid polymers, "carbomer" is the generic name for this type of polymer and, accordingly, the identification/description is indefinite.
Claim Rejections - 35 USC § 102
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 (i.e., changing from AIA to pre-AIA ) 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.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
A. First 35 U.S.C. 102 Rejection -
Claim(s) 1, 6 and 7 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by CL Denton, et. al, in “Pharmacokinetics and pharmacodynamics of AZD6244 (ARRY-142886) in tumor-bearing nude mice” (pub’d 04/21/2010; hereinafter “Denton”) and as evidenced by PubChem (Selumetinib CID of 10127622- exact structure) and Y. Li, et. al, in “Synergistic inhibition of MEK and reciprocal feedback networks for targeted intervention in malignancy” (Figure 1; hereinafter “Li”).
With respect to Claim 1, Denton discloses a MAPK/ERK kinase (MEK) inhibitor (pg. 349, col. 1, para. 1; AZD6244 (ARRY-142886) a novel small molecule MEK1/2 inhibitor) and phosphate buffered saline (PBS) (pg. 349, col. 2; AZD6244 for p.o. administration (which refers to oral medication administration) was made as a suspension in sterile filtered 1% Tween 80 in PBS by vortexing briefly) .
The drug name of AZD6244 is the synonym of Selumetinib (as evidenced by PubChem – pg. exact structure -it has a role as an EC 2.7.11.24 (mitogen-activated protein kinase) inhibitor) as well as a potent and selective oral medication that inhibits the MEK1/2 enzymes (also as evidenced by Li in Figure 1 below, the RAS-RAF-MEK-ERK signaling pathway - MAPK/ERK pathway - is a crucial cell signaling cascade that transmits signals from the cell surface to the nucleus, regulating cell growth, division, differentiation, and survival), which are part of the MAPK/ERK signaling pathway. AZD6244 reads on the Applicant’s election for a MAPK/ERK kinase (MEK1/2) inhibitor 2 and also reads on Independent Claim 1.
With respect to Claim 6, wherein the MAPK/ERK kinase (MEK) inhibitor is a MEK1 or MEK2 inhibitor (pg. 349, col. 1, para. 1; AZD6244 (ARRY-142886).
With respect to Claim 7, wherein the MEK1 or MEK2 inhibitor is selumetinib (pg. 349, col. 1, para. 1; AZD6244 (ARRY-142886).
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B. Second 35 U.S.C. 102 Rejection -
Claim(s) 1, 3-5, 8 and 9 are rejected under are rejected under 35 U.S.C. 102(a)(1) & 102(a)(2) as being anticipated by US 7,354,939 B2 (pub’d 04/08/2008; hereinafter “Patent’939”), and as evidenced by PubChem (Ulixertinib CID of 11719003 - exact structure) and Y. Li, et. al, in “Synergistic inhibition of MEK and reciprocal feedback networks for targeted intervention in malignancy” (Figure 1; hereinafter “Li”).
With respect to Claim 1, Patent’939 discloses the MAPK/ERK kinase inhibitor (col. 9, lns. 45-55; Compound I-9: exact structure – see below) and phosphate buffered saline (PBS) (col. 26, lns. 27-33) .
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The compound Structure I-9 is Ulixertinib (as evidenced by PubChem, pg. 1-2; exact structure; as an oral cancer drug that inhibits ERK1 and ERK2 proteins; the mechanisms of the MAPK pathway drives tumor cell growth), a treatment that inhibits ERK1/2 enzymes, caused by aberrant activation of the MAPK/ERK signaling pathway (also as evidenced by Li - Figure 1, seen above), the RAS-RAF-MEK-ERK signaling pathway (MAPK/ERK pathway) is a crucial cell signaling cascade that transmits signals from the cell surface to the nucleus, regulating cell growth, division, differentiation, and survival. Cancers bearing genetic mutations result in changes of the downstream components ERK (MAPK1 and MAPK3) and MEK (MAP2K1 and MAP2K2). All which read on the scope of the claims.
Structure I-9 reads on the Applicant’s election for a ERK kinase inhibitor and fulfills the intended use for Independent Claim 1; the activity of the compound utilized as an inhibitor of ERK1 and/or ERK2 protein kinases. This prior art “envisions the quaternization of any basic nitrogen-containing groups of the compounds…Water or oil-soluble or dispersable products may be obtained by such quaternization” (col. 25, lns. 65-67 to col. 26, lns. 1-2). Envisioning dispersible products involves creating formulations that can be easily dispersed in a liquid, such as water or a buffer; seen in the prior art as a pharamceutically acceptable carrier, adjuvant or carrier” (col. 26, lns. 11-55).
Patent’939 discloses in Example 6 (col. 46, lns. 20-40) and 7 (col. 46, lns. 45-60), a concentration of activated ERK2 compound (10 nM) used to determine inhibition. It also teaches the preparation of the phosphate prodrug of compound I-9, which is the Applicant’s election, synthesized to act as a carrier to improve the delivery and performance of the active drug, making it capable of its intended use. Determination of inhibition was seen for ERK2 protein kinase at <0.1 µM and at <0.01 µM. Both ERK kinase inhibitions with an IC50 of (<0.1µM) (or (<100nM) is considered strong or potent inhibitor.
With respect to Claim 3, further comprising a pharmaceutically acceptable excipient (col. 26, lns. 27-33).
With respect to Claim 4, wherein the excipient is polyols (col. 27, lns. 47-62).
With respect to Claim 5, provided in a suitable carrier (col. 26, lns. 27-33; col. 27, lns. 35-40), or formulated for topical administration (col. 29, lns. 34-45).
With respect to Claim 8, wherein the MAPK/ERK kinase (MEK) inhibitor is an ERK inhibitor (col. 9, Compound I-9; as evidenced by PubChem and Li).
With respect to Claim 9, wherein the ERK inhibitor is Ulixertinib (col. 9, Compound I-9 and as evidenced by PubChem). Patent’939 also discloses in Examples 6 and 7 (col. 46) - Ulixertinib potent inhibition against human tumor cell lines in formulations, particularly those activating mutations in the MAPK signaling pathway, consistent with its mechanism of action for this compound.
Claim Rejections - 35 USC § 103
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 (i.e., changing from AIA to pre-AIA ) 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.
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.
Claim 2 is rejected under 35 U.S.C. 103 as being unpatentable over Denton and in view of S. Kitajima in “Overcoming Resistance to Dual Innate Immune and MEK Inhibition Downstream of KRAS”(pub’d 09/10/2018; hereinafter “Kitajima”) as evidenced by CDER .
The teachings of Denton are disclosed above and at least those teachings are incorporated by reference herein.
With respect to Claim 2, the claim recites “…further comprising about 0.1 % to 20% DMSO and about 1% to about 20% HPMC and the MAPK/ERK kinase (MEK) inhibitor is a concentration of about 0.1 to about 10
µ
M or about 10% to 50% poloxamer 407 and about 1% to about 20% MEK inhibitor.” .
With regard to the claim ranges, Denton teaches varying concentration to suit the particular need of the experimentation. Although the prior art teaches the components of the composition, Denton fails to teach the concentration/amounts of Selumetinib relative to DMSO and HMPC.
However, use of Selumetinib in Denton meets the functional limitation because concentration is a result effective variable and routine optimization of rate, and/or concentration leads to different concentration percentages for the inhibitor. One could readily optimize the composition ranges to arrive at Claim 2’s meeting the instant functional limitation.
Kitajima though, teaches “MAPK and innate immune signaling pathways are tightly linked by feedback regulation. For example, treatment of K-Ras mutant NSCLC cells with the MEK inhibitor selumetinib (pg. 440, col. 1, paras. 2-3; also Applicant’s election) induces IL-6/STAT3 activation,…” which speaks to the scope of the Instant Specification (para. [0005]) “Mitogen-activated protein kinase (MEK1/MEK2) is a kinase in the Ras-MAPK pathway which phosphorylates and activates MAPK (mitogen-activated protein kinase)”.
Kitajima further discloses in an animal study (pg. e3-Animal Studies) overcoming resistance to dual innate immune and MEK inhibition. Of the MEK inhibitors, the prior art supports MEK inhibitors treating cancer. As seen in Figure 1A and 1G (pg. 441, 1G), tumor genes were treated with vehicle, 2 mg/kg trametinib (Tram), or 10 mg/kg MMB + 2 mg/kg Tram. “Trametinib was dissolved in 0.5% hydroxypropyl methyl cellulose (HPMC) and dose was 2 mg/kg daily by oral gavage.” Figure 1A and 1G demonstrate tumor change versus growth inhibition, as well as the change in tumor volume with mediums of HMPC, MEK inhibitor solo, and in combination. Administration indicates use of the API drug as treatment. This links the prior art to the scope of the claims by: 1. Use of an MEK inhibitor on tumor cells. 2. The MEK inhibitor used is a DMSO solvate and 3. The MEK inhibitor was dissolved in hydroxypropyl methyl cellulose (HPMC).
Therefore it would be obvious to one in the art, according to KSR – Prong B, to substitute the Tremetinib used in the prior art, with the applicant’s election of Selumetinib. Tremetinib and Selumetinib are both soluble in DMSO, are MEK inhibitors (working on the same mechanistic pathways of MAPK-ERK), and can be dissolved in hydroxypropyl methylcellulose (HPMC), as seen by the prior art.
Also, according to KSR-Prong A, one skilled in the art could combine known methods/composition of these MEK inhibitors since they have been known in the field since (Selumetinib) 2003 and (Trametinib) 2013. Based on that, one could combine known excipients, like HPMC, since they are known in the art as suggested by Denton and Kitajima publications to arrive at the instant combination of agents in the claims.
In this case because changes in concentration of MEK inhibitor, DMSO and HPMC impact solubility it is obvious to optimize a result effective variable because it is routine optimization to a skilled artisan. See MPEP 2144.05 (incorporated by reference herein).
Conclusions
Claims 1-9 are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Josmalen M. Ramos-Lewis whose telephone number is (571)272-0084. The examiner can normally be reached M-F 9:30-5:30 pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Clinton A. Brooks can be reached at (571) 270-7682. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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Josmalen M. Ramos-Lewis, Ph.D.
Patent Examiner
Art Unit 1621
/CLINTON A BROOKS/Supervisory Patent Examiner, Art Unit 1621