DETAILED ACTION
Status of Claims
The amendment submitted February 10, 2026 has been entered.
Claims 1-12, 15-26 are pending and under consideration.
Claims 1-12,15-23, and 26 are amended by Applicant.
Claims 13-14 are cancelled by Applicant.
Claims 1-12 and 15-26 are under consideration and the subject of this office 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 .
Election/Restrictions
Applicant’s election of Compound A (Rineterkib) as a species of ERK1/2 inhibitor, ruxolitinib as a species of active agent and myelofibrosis as a species of myeloproliferative neoplasm in the reply filed on March 3, 2026 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
For the purposes of compact prosecution, the search was expanded.
Claims 1-12 and 15-26 are under consideration and the subject of this Office Action.
Priority
This application is a 371 National Phase Application of PCT/IB2021/059203 filed October 7, 2021, which claims the benefit of 63/089172, filed on October 8, 2020.
Information Disclosure Statement
Two information disclosure statements (IDS) submitted on March 3, 2026 and April 6, 2023 are acknowledged. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Specification
Claim Objections
Claim 11 is objected to because of the following informalities: at line 2, claim 11, instead of “claim 1 any one of the claims 1 to 8,” it should read as claim 1. That is, “any one of the claims 1 to 8” should be deleted . Appropriate correction is required.
Claim Rejections - 35 USC § 102
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.
Claims 1-3, 8-10, and 15 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Stivala et al (Stivala et al. 2019. Targeting compensatory MEK/ERK activation increases JAK inhibitor efficacy in myeloproliferative neoplasms. The Journal of clinical investigation, 129(4), pp.1596-1611) as evidenced by Rein et al. (Rein, L.A., Wisler, J.W., Theriot, B.S., Huang, L.Y., Premont, R.T. and Lefkowitz, R.J., 2015. β-arrestin2 Is Necessary for Development of MPLW515L Mutant Primary Myelofibrosis. Blood, 126(23), p.486).
Regarding claims 1-2, Stivala teaches a method of treating myeloproliferative neoplasm in a patient comprising administering an ERK1/2 inhibitor in combination with at least one further active agent wherein the at least one further agent is a JAK2 inhibitor.”
Specifically, Stivala teaches studies where mice are treated by ruxolitinib and binimetinib. Ruxolitinib is a JAK2 inhibitor (page 1596, column 2, paragraph 2). Supplemental Figure 4 of Stivala shows that binimetinib inhibits ERK1/2; therefore, it is an ERK1/2 inhibitor.
Stivala uses two myeloproliferative neoplasm mouse models, JAK2V617F and MPLW515L, which are models of polycythemia vera (PV) and myelofibrosis (MF) (abstract)
MPLW515L is specifically known in the art to be a model for primary myelofibrosis (PMF). As evidenced by Rein, “Primary myelofibrosis (PMF) is a BCR-ABL negative myeloproliferative neoplasm (MPN) characterized by proliferation of myeloid cells and secondary development of marrow fibrosis due to release of growth factors from clonally expanded cells. PMF is characterized by mutations such as JAK2V617F and MPLW515L that lead to cytokine-independent cell growth and constitutive activation of downstream signaling pathways (abstract, Rein, L.A., Wisler, J.W., Theriot, B.S., Huang, L.Y., Premont, R.T. and Lefkowitz, R.J., 2015. β-arrestin2 Is Necessary for Development of MPLW515L Mutant Primary Myelofibrosis. Blood, 126(23), p.486).
Therefore, Stivala meets the limitations of claims 3 and 8, wherein the myelofibrosis comprises primary myelofibrosis.”
Claims 9-10 recite the limitations “wherein median survival time increased by at least 3 months after treatment,” and “wherein said patient achieves an Hb improvement of >/= 2.0g/dL or 1.5 g/dL after treatment,” which are directed to outcomes of administering the ERK1/2 inhibitor in combination with at least one further active agent.
As per MPEP 2111.04: “"‘whereby clause in a method claim is not given weight when it simply expresses the intended result of a process step positively recited.’" Id. (quoting Minton v. Nat’l Ass’n of Securities Dealers, Inc., 336 F.3d 1373, 1381, 67 USPQ2d 1614, 1620 (Fed. Cir. 2003)).”
In this instance, claims 9-10 recite outcomes resulting from administration of the combination therapy; therefore, do not require the practitioner to do anything materially different.
Regarding claim 15, Stivala’s method utilizes ruxolitinib as aforementioned; therefore, meeting the limitations of claim 15.
Consequently, Claims 1-3, 8-10, and 15 are rejected as being anticipated by Stivala.
Claim Rejections - 35 USC § 103
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.
Claims 1-12, 15-26 are rejected under 35 U.S.C. 103 as being unpatentable over Stivala et al (Stivala et al. 2019. Targeting compensatory MEK/ERK activation increases JAK inhibitor efficacy in myeloproliferative neoplasms. The Journal of clinical investigation, 129(4), pp.1596-1611) in view of Caponigro et al (USPN 10,973,829 B2).
The teachings of Stivala are applied as set forth above.
Stivala does not teach the limitations of claims 4-5 regarding patient populations with thrombocytopenia associated with myelofibrosis and neutropenia associated with myelofibrosis.
Stivala also does not Claims 6-7 recite the limitations “wherein said patient has a peripheral blood platelet count of less than or equal to 50,000/uL before treatment,” and “wherein said patient has a peripheral blood platelet count of less than or equal to 75,000/uL before treatment,”
Stivala also does not meet the limitations regarding patient populations with newly diagnosed MF as per claim 12.
Stivala also does not teach specific amounts and dosing schedule for ruxolitinib as per claim 16-17; however, does teach administration to mice and dosing based on body weight (page 1598, Figure 1), which is standard in the art of pharmacology to optimize based on patient population.
Stivala also does not teach the limitations of claims 18-19 “wherein the patient is receiving or has received prior therapy with ruxolitinib,” and the prior therapy amounts.
As per MPEP 2144.05.II.A: “Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955).”
Therefore, a person of ordinary skill in the art of oncology would be motivated to optimizing dosing and dosing schedule based on the individual patient to arrive at instant invention. Applicant has not provided any support for the criticality of the ranges claimed, particularly no guidance pertaining how to optimize methods with respect to patient population and factors such as age, body weight, etc.
Stivala also does not teach combination therapies using ruxolitinib with Compound A (Rineterkib); however, does teach combination therapies to treat identical conditions using ERK1/2 inhibitors with ruxolitinib.
Caponigro teaches Compound B, which is also known as Compound A or Rineterkib.
Caponigro teaces that “Compound B is an inhibitor of extracellular signal-regulated kinases 1 and 2 (ERK 1/2). Compound B is known by the name of 4-(3-amino-6-((1S,3S,4S)-3-fluoro-4-hydroxycyclohexyl)pyrazin-2-yl)-N—((S)-1-(3-bromo-5-fluorophenyl)-2-(methylamino)ethyl)-2-fluorobenzamide…Compound B has been shown to be active as a single-agent therapy in models of various solid tumors, and was especially effective when used in combination with a second anticancer therapeutic agent (column 4, lines 41-46 and column 5, lines 1-15).”
Caponigro teaches that “In one embodiment, the invention features a method of treating (e.g., inhibiting, reducing, ameliorating, or preventing) a disorder, e.g., a hyperproliferative condition or disorder (e.g., a cancer) in a subject. The method includes administering to a subject, in combination with a c-RAF inhibitor, an ERK inhibitor; in certain embodiments, the c-RAF inhibitor is Compound A, and the ERK inhibitor is Compound B. Suitable dosages and administration schedules for using these compounds in such methods are described herein (column 7, lines 53-62).”
Caponigro and Stivala do not explicitly teach the elements of claims 23-26 regarding combination therapies and pharmaceutical combinations using Rineterkib and ruxolitinib.
However, as per MPEP 21344.06, “"It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980) (citations omitted).”
Stivala does teach combination therapy using an ERK1/2 inhbitor in combination with JAK2 inhibitor to treat myelofibrosis and Caponigro does teach Rineterkib as an ERK ½ inhibitor for treating hyperproliferative disorders. Myelofibrosis is considered a hyperproliferative disorder. Consequently, the idea of substituting the ERK1/2 inhibitor binimetinib as recited in Stivala for Rineterkib or combining Stivala’s methods with Caponigro’s methods logically flows from their individual teachings in the prior art.
Consequently, re Kerkhoven, an ordinarily skilled artisan would arrive at the idea of the methods to form the instant invention as the result of a logical flow based on rineterkib and ruxolitinib having been taught individually in the prior art as suitable for the same purpose.
A person of ordinary skill in the art would have been motivated since it is prima facie obvious to combine components known for the same purpose for their combined additive effects, with a reasonable expectation of success absent evidence of criticality of the specific composition.
Additionally, a person of ordinary skill in the art would have arrived at the dosing, dosing schedule, and treatment regimen as a result of routine optimization as a highly predictable result in developing combination therapy treatment regimens based on the individual subject and other common parameters well-known in the pharmaceutical arts tailored towards a patient’s cancer needs and in order to achieve optimal efficacy for the patient.
Therefore, it would have been prima facie obvious for one of ordinary skill in the art to have modified the combination therapy methods taught by Stivala because Stivala teaches methods of combination therapy using an ERK1/2 inhibitor in combination with JAK2 inhibitor ruxolitinib to treat myelofibrosis and because Caponigro teaches that Rineterkib is an ERK1/2 inhibitor that can be used in combination therapies to treat hyperproliferative disorders.
An ordinarily-skilled artisan would have been additionally motivated to optimize the dosing and dosing schedules based on the patient populations as claimed as part of routine optimization as is standard in oncology to develop an effective treatment plan and part of achieving effective combination therapy regimens and to optimize according to the patient populations.
Therefore, a person of ordinary skill in the art would have arrived at the instant methods as a predictable result with a reasonable expectation of success based on the beneficial teachings of Stivala and Caponigro.
Consequently, claims 1-12, 15-26 are rejected on grounds of obviousness.
Conclusion
Claims 1-12, 15-26 are under consideration and are rejected. No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CAROLYN L. LADD whose telephone number is (703)756-5313. The examiner can normally be reached M-Th, 7:00 am to 5:30 pm EST.
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/C.L.L./Examiner, Art Unit 1622
/JAMES H ALSTRUM-ACEVEDO/Supervisory Patent Examiner, Art Unit 1622
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