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
Final Rejection
Claim Status
Claims 1-9 and 11-21 were pending as of the last Office Action.
Upon amendment entrance, Claims 1-2 and 4 were amended.
Upon amendment entrance, Claim 3 is cancelled.
Claims 1-2, 4-10 are pending examination.
Priority Status
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No foreign priority was claimed in the Instant Application; EFD is 04/29/2019.
Review of Restriction Requirements
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.
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.
Examiner Responses to Arguments/Amendments
The issues raised in the prior Office Action are addressed below:
I. Claim Objections –
In view of Applicant’s amendment, the objection to Claims 1 and 8 distinguish between MEK kinase inhibitors and ERK kinase inhibitors, is withdrawn.
II. Claim Rejection 35 U.S.C. § 112 –
In view of Applicant’s amendment, the rejection to Claim 4 for reciting the trademark/trade name "Carbopol", is withdrawn.
III. Claim Rejection 35 U.S.C § 102 –
Claims 1, 6, and 7 were rejected by Denton et al. (Cancer Chemother Pharmacol. 67:349-360, 2011) as evidence by Li et al. (Cancer Biol. Med. 16(3):415-434, 2019).
Claims 1, 3-5, and 8-9 were rejected under 35 U.S.C. § 102(a)(1) & 102(a)(2) by U.S. Patent No. 7,354,939 to Martinez-Botella et al. (hereinafter "Patent '939") as evidenced by PubChem (Ulixertinib CID:11719003) and further in view of Li et al. (Cancer Biol. Med. 16,3:415-434, 2019).
Applicant' s arguments, filed, with respect to claims have been fully considered but they are not persuasive.
Applicant argues “Denton et al. does not anticipate claim 1 as amended. First, Denton et al. does not disclose an ophthalmic comprising a MEK kinase inhibitor with an ophthalmic excipient, and does not teach administering a MEK kinase inhibitor in an ophthalmic composition as recited by claim 1.”
Examiner disagrees. In response to Applicant’s argument that Denton does not anticipate Instant Claim 1. The structure listed in Denton, is chemically and structurally exact as that in the Instant Claims. The structure performs substantially the same function, in substantially the same way, to achieve the same result as the claimed element. The labels do not change the core function. 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).
Applicant argues: “Denton et al. does not disclose an "ophthalmic composition" as claimed. The entire disclosure by Denton et al. is directed to oral administration of Selumetinib to tumor-bearing nude mice for cancer treatment.”
Examiner disagrees. In response to Applicant’s argument that Denton does not disclose the ophthalmic composition. If the prior art discloses the same chemical components and proportions, the composition itself is anticipated under 35 U.S.C. 102, regardless of the intended target organ or use. 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).
Additionally, a known chemical composition or formulation does not become novel simply because of a new method or route of administration (such as oral instead of topical eye use). Properties or results that naturally flow from a prior art composition—such as systemic absorption or safe ingestion of an excipient blend—are inherent As indicated in the prior Office Action on pg. 6:
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Applicant argues: “the preamble of claim 1 recites "[a]n ophthalmic composition," which imparts a specific meaning to the claimed invention. The '939 Patent does not teach any specific examples of formulations, and does not teach excipients that are specifically contemplated as an "ophthalmic excipients." An ophthalmic composition must be suitable for ophthalmic use, which requires specific formulation considerations for ocular tolerability, sterility, pH, osmolality, and compatibility with ocular tissues.”
Examiner disagrees. In response to Applicant’s argument that the ophthalmic composition is not taught. On col. 29, lns. 34-42 of Patent’939 the following is disclosed:
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The claimed property is not newly discovered or unique, but a baseline, inherent characteristic already known in the field. The applicant claims that criticality exists, but the submitted evidence shows no proof of this claim. The records and data provided only display normal conditions with zero critical findings. Because the applicant has not met the required burden of proof with objective evidence, the argument is not persuasive.
The 35 U.S.C § 102’s Claim Rejections are maintained.
IV. Claim Rejections 35 U.S.C § 103 –
Applicant argues: “The Examiner's rationale for combining Denton et al. and Kitajima et al. fails because neither reference provides any motivation to formulate a MEK kinase inhibitor as an ophthalmic composition. The Examiner's KSR substitution rationale-substituting selumetinib for trametinib-does not bridge the gap between systemic orally administered compositions for cancer treatment and the claim-recited ophthalmic compositions. There is no suggestion in either reference that MEK kinase inhibitors could or should be formulated for topical ocular administration.”
Examiner disagrees. 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).
The 35 U.S.C § 103 Claim Rejections are maintained.
V. Maintained Rejections -
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 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) and an ophthalmic excipient (col. 29, lns. 34-42).
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, 4-5, 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 dispersible 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 pharmaceutically acceptable carrier (col. 26, lns. 27-33), 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 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
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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.
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 Josmalen M. Ramos-Lewis whose telephone number is (571)272-0084. The examiner can normally be reached M-F 9:30-5:30 pm.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
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
Prosecution Insights